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Advances in Targeted Therapy for Small  Cell Lung Cancer

Future Potential in Combination Therapies

Video content above is prompted by the following:

What PFS and OS end points would you typically expect from second- or third-line therapy in your previously treated patients with relapsed/refractory SCLC?

Videos

Panelists discuss advances in targeted therapy for small cell lung cancer (SCLC), focusing on the impact of recently approved therapies on survival benefits, the mechanisms of DLL3-directed bispecifics, and the integration of these therapies into updated NCCN guidelines for extensive stage SCLC.

Panelists discuss how managing extensive stage small cell lung cancer involves balancing the survival benefits of subsequent therapies with the risks of treatment-related adverse events, emphasizing the importance of individualized treatment strategies.

Clinical Impressions and Therapy Goals

Dr. Sabari discusses how, for extensive stage small cell lung cancer (ES-SCLC) that progresses within six months after platinum-based chemoimmunotherapy and immunotherapy maintenance, options like lurbinectedin, topotecan, and irinotecan are considered viable subsequent treatments due to their proven effectiveness in similar clinical scenarios.

Considerations for Extended Chemoimmunotherapy

Joshua K. Sabari, MD, discusses how, despite negative results from serial brain MRIs, the consideration of PCI in patients with ES-SCLC depends on individual risk factors, including the likelihood of brain metastases and the overall treatment strategy aimed at improving outcomes.

Prophylactic Cranial Irradiation Considerations

Joshua K. Sabari, MD, discusses how tarlatamab, a BiTE, demonstrates a unique mechanism of action by targeting DLL3, which is aberrantly expressed in 85% to 94% of SCLC cells, thereby directing T cells to these cancer cells independently of MHC class I and promoting T-cell–mediated tumor lysis and regression.

Mechanism of Action of BiTE Immunotherapy

Joshua K. Sabari, MD, discusses how the ORR of 32% to 40% observed in the DeLLphi-301 clinical trial among participants receiving tarlatamab is clinically meaningful, particularly given that these responses occurred between 5 and 7 weeks after initiation and emphasize the importance of ORR as a primary end point in evaluating the efficacy of treatment in this patient population.

Interpreting DeLLphi-301 Trial Results: ORR, Duration of Response, and Long-Term Outcomes

Joshua K. Sabari, MD, discusses how, despite the relatively small numbers of CRs and PRs in the DeLLphi-301 trial, the DOR to tarlatamab (exceeding 6 months in 59% of patients and more than 9 months in 29%) is promising, particularly considering that more than 50% of responders maintained their response at the data cutoff, indicating potential long-term benefits in this treatment setting.

Significance of Durable Responses in DeLLphi-301 Trial

Joshua K. Sabari, MD, discusses the expected PFS of 3 to 6 months and OS of 6 to 12 months for second- or third-line therapy in previously treated patients with relapsed/refractory SCLC.

Expectations for PFS and OS in Relapsed/Refractory SCLC

Joshua K. Sabari, MD, discusses the future treatment potential of tarlatamab as a combination therapy with other anticancer agents for previously treated SCLC, suggesting that it could enhance efficacy and improve patient outcomes following 2 or more lines of prior therapy.

Joshua K. Sabari, MD, discusses the anticipated clinical benefits of adding tarlatamab to durvalumab as maintenance therapy for patients with ES-SCLC, highlighting that statistically significant trial end points, such as improved PFS and OS, could encourage community oncologists to adopt this dual maintenance approach.

Dual Maintenance With BiTE and PD-L1 Inhibitors

Joshua K. Sabari, MD, discusses the unique mechanism of action of B7-H3, highlighting its role as an immune checkpoint regulator that is overexpressed in SCLC and associated with poor prognosis. He notes that B7-H3 blockade can enhance CD8-positive T-cell activity and may serve as a promising treatment option for SCLC that has progressed after platinum-based chemotherapy.

B7-H3 Mechanism and Therapeutic Potential

Joshua K. Sabari, MD, discusses whether individual B7-H3 analysis is available at his institution, noting that, if it is, he obtains IHC for both PD-L1 and B7-H3 expression levels in all patients with SCLC. If B7-H3 testing becomes available, he would consider adding it to the biomarker assay, particularly at the time of diagnosis or recurrence.

Current Practices in B7-H3 Testing

Joshua K. Sabari, MD, discusses the efficacy outcomes from the Ideate-Lung02 trial, noting the 52.4% ORR, 5.9-month median DOR, and 12.2-month OS and emphasizing that a 12-month OS is clinically meaningful for this patient population following a median of 2 prior lines of therapy.

Interpreting IDeate-Lung02 Trial Outcomes

Joshua K. Sabari, MD, discusses how the dosing schedule of ifinatamab deruxtecan offers advantages in terms of simplicity and treatment adherence vs topotecan and lurbinectedin, suggesting that it may enhance the overall quality of life for patients undergoing treatment for SCLC.

Comparing Dosing Schedules With Standard Therapies

Joshua K. Sabari, MD, discusses the potential treatment synergies expected from combining MK-6070, a trispecific T-cell engager, with ifinatamab deruxtecan, noting that specific patient and disease factors (eg, tumor expression profiles and previous treatment responses) could influence the decision to pursue dual T-cell engager therapy in early clinical development.

Potential Synergies With T-Cell Engagers

Joshua K. Sabari, MD, evaluates the potential of ifinatamab deruxtecan in combination with atezolizumab, with or without platinum-based chemotherapy, as first-line induction or maintenance therapy in ES-SCLC, emphasizing that statistically significant end points such as improved PFS and OS would be essential for clinical application in this patient population.

Prospects in First-Line and Maintenance Settings

Joshua K. Sabari, MD, describes the mechanism of action of lurbinectedin as a synthetic alkaloid that binds to guanine residues in the minor groove of DNA, forming adducts that disrupt DNA repair mechanisms and promote apoptosis in cancer cells, noting that its action contrasts with traditional alkylating agents by specifically interfering with DNA-protein interactions and transcription processes.

Mechanism of Action Compared With Other Alkylating Agents

Joshua K. Sabari, MD, discusses the antitumor activity of second-line lurbinectedin, noting an ORR of 45%, a median DOR of 6.2 months, and a median OS of 11.2 months in patients with relapsed SCLC, and emphasizes the need for further studies to validate these findings in those with longer chemotherapy-free intervals while considering factors that may lead to lurbinectedin’s use over chemotherapy in candidates for platinum rechallenge, as well as the potential role of G-CSFs for prophylaxis.

Efficacy in Platinum-Sensitive vs Platinum-Resistant SCLC

Joshua K. Sabari, MD, evaluates the objective clinical outcomes of emerging targeted therapies for ES-SCLC, comparing them with second-line topotecan and CAV regimens, while discussing the potential of various compounds for platinum-sensitive vs platinum-resistant subgroups. He also considers the applicability of TIGIT immunotherapy, highlighting the need for robust clinical trial data on its safety and efficacy as both monotherapy and in combination, and he reflects on whether tiragolumab is more suited for chemotherapy-naive non–small cell lung cancer than for ES-SCLC, based on the phase 2 CITYSCAPE trial results.

Comparative Efficacy and Future Directions in SCLC Treatment

Case Based Peer Perspectives

Future Potential in Combination Therapies

EP: 1.Clinical Impressions and Therapy Goals

EP: 2.Considerations for Extended Chemoimmunotherapy

EP: 3.Prophylactic Cranial Irradiation Considerations

EP: 4.Mechanism of Action of BiTE Immunotherapy

EP: 5.Interpreting DeLLphi-301 Trial Results: ORR, Duration of Response, and Long-Term Outcomes

EP: 6.Significance of Durable Responses in DeLLphi-301 Trial

EP: 7.Expectations for PFS and OS in Relapsed/Refractory SCLC

EP: 8.Future Potential in Combination Therapies

EP: 9.Dual Maintenance With BiTE and PD-L1 Inhibitors

EP: 10.B7-H3 Mechanism and Therapeutic Potential

EP: 11.Current Practices in B7-H3 Testing

EP: 12.Interpreting IDeate-Lung02 Trial Outcomes

EP: 13.Comparing Dosing Schedules With Standard Therapies

EP: 14.Potential Synergies With T-Cell Engagers

EP: 15.Prospects in First-Line and Maintenance Settings

EP: 16.Mechanism of Action Compared With Other Alkylating Agents

EP: 17.Efficacy in Platinum-Sensitive vs Platinum-Resistant SCLC

EP: 18.Comparative Efficacy and Future Directions in SCLC Treatment