Advancing Care in Small Cell Lung Cancer: Optimizing Immunotherapy, Managing Toxicities, and Exploring Emerging Therapies

Panelists discuss how durvalumab consolidation after chemoradiation has become the standard of care for limited-stage SCLC based on the ADRIATIC trial, with most patients being considered candidates for the 2-year treatment course.

Panelists discuss how patient selection for durvalumab consolidation requires careful consideration of autoimmune diseases, baseline lung function, and neurologic paraneoplastic syndromes, while emphasizing that most patients should receive immunotherapy unless they have severely active contraindications.

Panelists discuss how pneumonitis risk management requires intensive patient education about symptoms, close monitoring for several months post radiation, and multidisciplinary coordination with pulmonology and radiation oncology teams to distinguish between radiation-induced and immunotherapy-related pneumonitis.

Panelists discuss how the concerning underutilization of first-line chemoimmunotherapy in extensive-stage SCLC may stem from clinical nihilism, lack of urgency in treatment initiation, and inadequate education about the substantial benefits these therapies provide to patients.

Panelists discuss how while emerging biomarkers like inflamed subtypes and MHC class I expression show promise for predicting immunotherapy benefit, current clinical practice treats all patients with immunotherapy since the potential for exceptional responses cannot be reliably predicted.

Panelists discuss how preliminary neoadjuvant chemoimmunotherapy data showing high response rates and pathologic complete responses in limited-stage SCLC appears promising but requires larger studies and careful patient selection given the complexity of staging and surgical candidacy.

Panelists discuss how managing toxicities during chemoradiation requires proactive counseling about esophagitis and fatigue, while immunotherapy consolidation typically doesn’t enhance these acute toxicities, making it feasible to start within the recommended timeframe after completion of chemoradiation.

Panelists discuss how monitoring for long-term immunotherapy toxicities requires regular imaging and symptom assessment, with early recognition and treatment of pneumonitis, hypothyroidism, and adrenal insufficiency being critical for maintaining patients on therapy and preventing chronic complications.

Panelists discuss how neutropenia management varies widely across institutions, with some using primary prophylaxis with G-CSF or trilaciclib, while others tailor supportive care based on individual patient risk factors including age, comorbidities, and prior treatment tolerance.

Panelists discuss how tarlatamab implementation requires careful infrastructure planning, including 24-hour monitoring capabilities, staff education about cytokine release syndrome management, patient counseling, and coordination with community partners to ensure all eligible patients have access to this standard-of-care therapy.

Panelists discuss how antibody-drug conjugates targeting B7-H3 show impressive response rates compared to historical controls, while T-cell engagers remain the priority for second-line therapy due to their demonstrated durability, though patient preferences and contraindications may influence individual treatment decisions.

Panelists discuss how emerging therapies including DLL3-targeted ADCs, trispecific T-cell engagers, CAR T cells, and radioligand therapies represent promising approaches that may offer single-dose treatments or enhanced efficacy, though more data on durability and optimal sequencing are needed.

Panelists discuss how the next 3 to 5 years will likely see T-cell engagers moving into earlier treatment lines, potential ADCs replacing chemotherapy in first-line therapy, and the critical need for better biomarker testing to optimize treatment sequencing and patient selection in an increasingly complex therapeutic landscape.

Dr. Afshin Dowlati introduces the discussion by outlining the phase 2 IDeate-Lung01 trial, which evaluated ifinatamab deruxtecan (I-DXd) in patients with extensive-stage small cell lung cancer who had baseline brain metastases. He explains that the study began with a dose-escalation phase followed by dose expansion, during which patients received either 8 mg/kg or 12 mg/kg intravenously every three weeks. The final dosing selected for the expansion cohort was 12 mg/kg every three weeks. Dr. Dowlati details the imaging schedule, noting that all patients underwent baseline brain scans and those with brain metastases received follow-up MRIs every six weeks for 36 weeks and then every 12 weeks. Central nervous system responses were assessed using RECIST 1.1 criteria modified for brain tumor evaluation.

Dr. Dowlati reviews the primary results from IDeate-Lung01 as of the March 3, 2025 data cutoff. Among 137 patients treated with ifinatamab deruxtecan at 12 mg/kg, 65 (47%) had baseline brain metastases. Of these, 29 patients (45%) had measurable target lesions and 26 (40%) had not received prior brain radiation. The confirmed CNS objective response rate was 46.2% overall, increasing to 65.5% in patients with measurable target lesions and 57.7% among those without prior radiation, demonstrating meaningful intracranial activity even in untreated brain lesions. Safety outcomes were similar between patients with and without brain metastases, with grade 3 or higher treatment-related adverse events reported in 31% versus 42% of patients, respectively. Dr. Dowlati emphasizes that the presence of brain metastases did not increase toxicity risk with I-DXd treatment.

Dr. Dowlati contextualizes the IDeate-Lung01 findings by emphasizing how common brain metastases are in small cell lung cancer, affecting up to 80% of patients during the disease course. He praises the trial investigators for specifically evaluating intracranial outcomes, noting that ifinatamab deruxtecan demonstrated strong activity in the brain, with response rates above 50% even in patients who had not received prior radiation. This level of activity is comparable to systemic response rates seen with first-line chemotherapy and similar to results from other antibody–drug conjugates in development. Dr. Dowlati highlights that treatment with I-DXd did not lead to higher toxicity and achieved a 91% CNS disease control rate, a median intracranial response duration of 6.2 months, and a median time to response of 1.4 months. In patients without prior brain radiation, the CNS disease control rate was 92% with a median response duration of 6.7 months, supporting I-DXd’s potential as an effective and well-tolerated therapy for patients with and without prior brain-directed treatment.

Dr. Dowlati concludes by affirming that the IDeate-Lung01 trial was thoughtfully designed and executed, incorporating critical assessment of brain metastases to evaluate intracranial efficacy. He summarizes that ifinatamab deruxtecan achieved high, rapid, and durable intracranial response rates comparable to systemic outcomes, with strong disease control and no additional toxicity in patients with baseline brain metastases. These findings support I-DXd as a promising therapy for patients with extensive-stage small cell lung cancer, including those with CNS involvement. Dr. Dowlati reflects on the broader implications of these results, suggesting that as systemic agents with significant intracranial activity become available, the traditional role of brain radiation—particularly whole-brain or stereotactic radiotherapy—may need to be reconsidered. He emphasizes that future research should explore whether effective systemic therapies like I-DXd could safely delay or reduce the need for brain-directed radiation in this population.