Small Cell Lung Cancer

Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4 and 6 inhibitor approved for reducing the incidence of chemotherapy-induced myelosuppression in adult patients with extensive-stage small cell lung cancer receiving a platinum/etoposide-containing or topotecan-containing regimen. Ad hoc analysis using National Cancer Institute classification showed similar results. The US Food and Drug Administration-approved trilaciclib dose of 240 mg/m2 should be reduced by ∼30%, to 170 mg/m2, for patients with moderate or severe HI.

P2, N=60, Not yet recruiting, Beijing Chest Hospital, Capital Medical University

P2, N=100, Recruiting, The University of Sydney | Not yet recruiting --> Recruiting

In particular, three miRNAs has-miR-26a-5p, has-miR-26b-5p and has-miR-29b-3p fine tune the p53 and cell cycle signaling pathways to regulate DPSC cellular activities. The work indicated that miRNAs are promising targets to modulate stem cell regeneration and understanding miRNA-targeted genes and their associated pathways in smoking individuals have significant implications for disease control and prevention.

P1/2, N=56, Active, not recruiting, Sarcoma Oncology Research Center, LLC | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

The addition of tiragolumab, an anti-TIGIT inhibitor, to chemotherapy plus atezolizumab demonstrated promising early results for lung cancer. Unfortunately, the phase 3 study SKYSCRAPER-02 did not confirm the anticipated benefit of tiragolumab combination in recalcitrant small-cell lung cancer,1 reiterating the need for a more accurate population selection in clinical trials.

Then, we update the current clinical evidence with immune checkpoint blockade and review other emerging immunotherapy strategies that are gaining increasing attention in SCLC. We finally summarize our future perspective on immunotherapy and precision oncology for this disease.

This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Pre-existing IFNg-driven immunity and mitochondrial metabolism seem correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.

HHLA2-positive SCLC patients had higher tumour stages and shorter 2-year survival times than HHLA2-negative patients did. The new immune molecule HHLA2 may be an ideal clinical biomarker for predicting SCLC progression and could serve as a new immunotherapy target in SCLC.

Osimertinib has become the first globally accessible third-generation EGFR inhibitor, representing one of the most advanced developments in non-small-cell lung cancer (NSCLC) therapy...These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition, and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the resistance, and mutations of EGFR, and then mainly focus on the recent advances of EGFR-targeting degraders along with its advantages and outstanding challenges.

CLDN4 could be considered as a predictive marker of recurrent MPE among patients with advanced NSCLC. Further validation for its clinical value in cohorts with larger sample size and in-depth mechanism studies on its biological function are warranted.

P=N/A, N=460, Recruiting, Duke University | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024

P2, N=17, Recruiting, Georgetown University | Not yet recruiting --> Recruiting

P2, N=61, Recruiting, Sichuan University | Not yet recruiting --> Recruiting

P1/2, N=263, Recruiting, Salubris Biotherapeutics Inc | N=149 --> 263

The combined assay of CYFRA21-1, NSE, and CEA addresses the aspects of accuracy, sensitivity, specificity, and economic cost and should be considered as a potential diagnostic test in LC.

Patients with higher comorbidity score were less likely to receive CIT, suggesting chemotherapy avoidance in comorbid patients. Larger tumours are associated with CIT use, indicating that oncologists may use tumour size as a surrogate of disease burden. Limitations include small sample size and data cut-off. Future prospective studies could incorporate comorbid status and a validated disease burden score to stratify patients.

P1/2, N=413, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

HE4 and its combined detection held substantial clinical significance in the diagnosis of lung cancer and its histologic subtyping, especially for lung adenocarcinoma and lung squamous cell carcinoma.

Chemoradiotherapy (CRT) followed by consolidation of immune checkpoint inhibitors (ICIs), such as durvalumab or pembrolizumab, for patients with unresectable, locally advanced non-small cell lung cancer (NSCLC) with tumor PD-L1 expression <1% remains a topic of controversy. The findings of the present study highlighted that the benefits of CRT followed by consolidation of ICIs were higher compared with CRT alone in patients with unresectable, locally advanced NSCLC and PD-L1 expression <1%. Consolidation of ICIs after CRT would provide greater benefits for locally advanced NSCLC patients with PD-L1 expression ≥1% compared with those with PD-L1 expression <1%.

P1/2, N=39, Recruiting, Novartis Pharmaceuticals | Phase classification: P1 --> P1/2

As non-SCLC (NSCLC) often transforms to SCLC following targeted therapy, we applied our framework to distinguish NSCLC from SCLC and achieved an AUC of 0.99. Our approach shows promising utility for SCLC subtyping and transformation monitoring, with potential applicability to diverse tumor types.

Combination of chidamide and envafolimab showed efficacy signals in certain NSCLC patients. But further identification of beneficial population is necessary for precision treatment.

However, Notch signaling may be activated after chemotherapy, and, in concert with Yes-associated protein signaling and RE1-silencing transcription factor, suppresses NE differentiation, producing intratumor heterogeneity and chemoresistance. Accumulated information on the molecular mechanisms of SCLC will contribute to further advances in the control of this recalcitrant cancer.

Persistence of the T790M gene mutation after the development of Osimertinib resistance is associated with higher therapeutic benefits of Osimertinib in NSCLC patients. The results of tissue detection are more significant than those of plasma detection.

P1/2, N=34, Suspended, University of Washington | Recruiting --> Suspended

P2, N=122, Active, not recruiting, National Cancer Institute (NCI) | Terminated --> Active, not recruiting | Trial completion date: Jun 2022 --> Apr 2025

P1/2, N=149, Not yet recruiting, Daiichi Sankyo

P1, N=90, Recruiting, NiKang Therapeutics, Inc. | Not yet recruiting --> Recruiting | Trial completion date: May 2027 --> May 2025 | Trial primary completion date: Jan 2027 --> Mar 2025

In real-world practice, CP demonstrated superior PFS compared with CNI. These findings can inform treatment selection in advanced NSCLC.

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P1, N=48, Active, not recruiting, Carisma Therapeutics Inc | Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2023 --> Dec 2024

PAX8 expression rate in SCLC specimens is not low. It has prognostic value in small cell lung cancer.

In vitro experiments confirmed that the expression of ADCY4 was significantly decreased after anti-PD1 antibody treatment, while the expression of energy metabolism factors were significantly different. This study reveals a potential mechanism by which ADCY4 mediates poor prognosis through energy metabolism -related pathways in SCLC.

Intriguingly, the FAK-LINC01089 interaction depends on the co-occurrence of the novel FAK variant and the non-conserved region of LINC01089 in primates. In Conclusion, our results indicated that LINC01089 may serve as a novel high-efficiency FAK inhibitor and the FAK-LINC01089 axis represents a valuable prognostic biomarker and potential therapeutic target in SCLC.

P1/2, N=18, Recruiting, Vanderbilt-Ingram Cancer Center | Trial completion date: Dec 2027 --> Jun 2028 | Initiation date: Jan 2024 --> Jul 2024 | Trial primary completion date: Dec 2026 --> Jun 2027

P=N/A, N=300, Recruiting, Jazz Pharmaceuticals | Active, not recruiting --> Recruiting | Trial completion date: Jan 2026 --> Jun 2030 | Trial primary completion date: Oct 2025 --> Jun 2030

Aurora kinase inhibitors such as alisertib can destabilize MYC-family oncoproteins and have demonstrated compelling anti-tumor efficacy. Furthermore, DBPR728 was found to synergize with the mTOR inhibitor everolimus to suppress c-MYC- or N-MYC- driven SCLC. Collectively, these results suggest DBPR728 has the potential to treat cancers overexpressing c-MYC- and/or N-MYC.

The combined SII-SP142 biomarker can be readily and universally obtained at a low cost in clinical practice, without requiring advanced genomics technology or specialized expertise. Although further studies are needed to confirm that the combined SII-SP142 biomarker is widely applicable, it should help clinicians to identify the best patients for combined chemotherapy with atezolizumab in ES-SCLC.

P2, N=382, Active, not recruiting, MacroGenics | N=100 --> 382 | Trial completion date: Dec 2026 --> May 2027 | Trial primary completion date: Dec 2026 --> May 2027