Why has no targeted drug been approved for Small cell lung cancer so far?
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Why has no targeted drug been approved for Small cell lung cancer so far?
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Why has no targeted drug been approved for Small cell lung cancer so far?
Has no targeted drug been approved so far? The dilemma and progress of targeted therapy for small cell lung cancer.
Small cell lung cancer (SCLC) is a refractory and poor prognosis lung cancer, accounting for about 15% of all lung cancer types.
It is characterized by rapid growth and early spread. The vast majority of patients are already in stage IV or extensive stage at the time of diagnosis ( ES).
The first-line standard EP/EC regimen for ES-SCLC has limited efficacy, with a median OS of 8-11 months.
The first-line immunization combination has shown good efficacy in SCLC, but as the indications of O drugs and K drugs in SCLC have been withdrawn, immunotherapy can be described as mixed.
In recent years, targeted therapy has become a research direction for the treatment of SCLC and has attracted wide attention. But so far, no targeted drugs have been approved.
This article summarizes the related research progress of SCLC targeted therapy, hoping to provide some reference or theoretical basis for the treatment of SCLC.
Why has no targeted drug been approved for Small cell lung cancer so far?
Tyrosine kinase inhibitor
First:
variety of receptor tyrosine kinase inhibitors have been studied in clinical trials in patients with SCLC. Unfortunately, most of the research results are negative.
In a phase II clinical study of a specific small molecule receptor tyrosine kinase inhibitor imatinib, approximately 70% of patients with recurrent SCLC enrolled highly express the c-Kit gene, but imatinib Did not draw a positive conclusion.
Similarly, the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib, gefitinib, afatinib, and the insulin-like growth factor 1 receptor tyrosine kinase inhibitor linsitinib did not significantly increase the OS of SCLC patients. And PFS.
Second:
Anlotinib is a new type of small molecule multi-target receptor tyrosine kinase inhibitor, which can effectively inhibit vascular endothelial cell growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and c- Kinase activity of the Kit receptor.
Based on the ALTER1202 study, the National Medical Products Administration has approved anlotinib hydrochloride for the third-line treatment of progressive or relapsed SCLC patients.
This approval also fills the gap in the domestic third-line treatment of SCLC, making anlotinib hydrochloride a domestic The only anti-angiogenic drug approved for both non-small cell lung cancer (NSCLC) and SCLC.
Third:
Recently, a prospective phase II clinical trial has further confirmed the efficacy and safety of anlotinib hydrochloride monotherapy in patients with relapsed SCLC after second-line and above systemic treatment.
The study included 45 patients from November 2018 to August 2019, with a median PFS of 4.1 months and a median OS of 6.1 months.
Of the 45 patients, 5 patients were evaluated as PR, 25 patients were evaluated as SD, and 15 patients were evaluated as PD. The final ORR was 11% (5 cases) and DCR was 67% (30 cases).
Common adverse reactions with an incidence ≥ 5% are hypertension (13%), decreased appetite (9%), fatigue (9%), nausea (7%), hand-foot syndrome (5%), hyperbilirubinemia (5%), thrombocytopenia (5%), leukopenia (5%), hemoptysis (5%), dizziness (5%). Hypertension of grade 3-4 can be well controlled by medication.
Notch signaling pathway inhibitor
The Notch signaling pathway is mostly uncontrolled in tumors, and affects tumor growth, tumor blood vessels and tumor immunity.
Notch has 4 receptor expressions (Notch 1-4) and 5 ligand expressions (DLL1, DLL3, DLL4 and Jagged1, Jagged2).
Among them, the high expression of DLL3 in SCLC and neuroendocrine cells is an ideal target for SCLC, which provides new ideas for SCLC targeted therapy.
Rova-T
The results of a phase I clinical trial of Rova-T in the treatment of SCLC patients are gratifying.
The study enrolled 74 patients with late recurrence of SCLC, of which 60 patients can be evaluated.
The results of the study show: Rova-T second-line treatment The ORR of DLL-3 positive SCLC patients was 40%, and the clinical benefit rate was 73%;
Rova-T third-line treatment of DLL-3 positive SCLC patients had an ORR of 38%, and the clinical benefit rate was 77%, indicating that Rova-T T has a very good effect in the second and third-line treatment of SCLC.
In 2016, the WCLC updated the results of the study. The median PFS of 60 patients was 2.8 months, the median OS was 4.6 months, and the 1-year survival rate was 18%;
26 patients with DLL-3 positive expression ≥ 50% Among the patients, 10 achieved remission, the median PFS was 4.3 months, the median OS was 5.8 months, and the 1-year survival rate was 29%.
In 2018, ASCO announced the results of a phase II clinical study of Rova-T. From March 2016 to July 2017, the study screened 1,358 patients, and 339 patients were enrolled and received at least one cycle of Rova-T treatment.
Among them, 85% and 70% of patients were assessed as DLL-3 positive and high expression, respectively.
The study found that the ORR of the total population, DLL-3 positive and high expression patients were 20.1% (95% CI: 15.9, 24.7), 20.6% (95% CI: 16.0, 25.7) and 21.8% (95% CI: 16.8) , 27.6).
Of the 20 patients who received additional Rova-T treatment, none were evaluated for CR or PR.
The median PFS, duration of treatment, and OS were 3.8 months, 4.0 months, and 5.7 months, respectively.
Among the 261 patients who received Rova-T as the third-line treatment, the overall ORR was 13%.
For patients with high and non-high DLL-3 expression, the ORR was 15.8% and 6.3%, respectively, and the median duration of response was 4.1. Months and 3.0 months.
The results of a phase III clinical trial of Rova-T as a maintenance treatment after standard etoposide + cisplatin chemotherapy showed: (Rova-T group vs topotecan) median OS: 6.3 months vs 8.6 months, HR=1.46 ( 95% CI: 1.17-1.82, p = 0.0051).
The OS results in the subgroup analysis showed consistent trends. Due to the shorter OS of Rova-T, the Independent Data Monitoring Committee recommended to stop joining the group.
Median PFS: 3.0 months vs 4.3 months, HR=1.51 (95%CI: 1.22-1.87); ORR: 15% vs 21%; mDOR: 3.5 months vs 4.9 months.
The incidence of adverse reactions (TEAE) during treatment in the two groups was 95% vs 97%, respectively. The incidence of severe TEAE in the two groups was 56% and 57%, respectively.
The quality of life score in the Rova-T group had a greater decline. Research conclusions: Compared with the current standard second-line chemotherapy regimen topotecan, Rova-T showed a lower OS and a higher incidence of serous effusion, photosensitivity and peripheral edema in SCLC patients.
AMG 757
At this year’s European Lung Cancer Conference (ELCC Virtual 2021), a new drug, AMG 757, showed good efficacy and safety, and became the focus of attention.
AMG757 is a bispecific antibody targeting DLL3 and CD3. DLL3 is the ligand of Notch, and CD3 antigen is an important marker on the surface of T cells.
T lymphocyte activation is the basis of immune response and one of the hot targets.
AMG757 binds to DLL3 and T cells in SCLC respectively, so that T cells can accurately bind to tumor cells, enhance immune response, and promote tumor cell lysis.
In preclinical studies, it was found that CD4+T cells and CD8+T cells in tumor tissues of SCLC PDX model tumor tissues increased significantly with AMG757 treatment, and T cell activation markers CD25, CD69, PD-1, etc. were significantly upregulated.
AMG757 treatment can see 83%-98% of tumors have retracted, and 80% of SCLC PDX tumors have a complete remission.
In the SCLC liver metastasis mouse model, liver metastases disappeared 23 days after AMG757 treatment. Pre-clinical results suggest that: AMG757 has strong anti-tumor activity on SCLC, suggesting that SCLC clinical research is a viable option.
This year’s ELCC conference announced the latest data of a multi-center, phase I clinical study.
As of November 3, 2020, the study included 52 patients with SCLC, all of whom had relapsed/refractory SCLC after receiving at least 1 line of platinum-based chemotherapy The median number of treatment lines was 2, 98% of patients had an ECOG PS score of 0 or 1. 44% of patients had previously received PD-1/PD-L1 inhibitor therapy, and 96% of patients had ES-SCLC at the time of initial diagnosis. 25% had brain metastases and 48% had liver metastases.
The study used dose escalation (0.003-30 mg q2w nine dose groups). The primary endpoint is safety and the recommended dose for phase II.
The results of the study showed that the confirmed partial response rate (PR) was 14%, and 1 patient had an unconfirmed PR; 22% of patients reached stable disease (SD), and the disease control rate (DCR) was 37%.
40% of patients have observed tumor shrinkage; 20% of patients have completed 24 weeks of treatment, and 4 confirmed PR patients are still receiving treatment, and the treatment response continues.
Among patients with confirmed PR (n = 7), the median time to disease remission was 1.8 months.
Among patients with a median follow-up of 11.5 months, 83% of patients had remission longer than 6 months. Further analysis showed that DLL3 high expression ORR was higher, reaching 38%.
The investigator of the study:
Although the study has set up 9 dose cohorts, the maximum tolerated dose of AMG 757 has not yet been reached, and the study is still going on to determine the phase II recommended dose.
In terms of safety:
79% and 23% of patients had all grades and ≥3 treatment-related adverse events (TRAE), respectively.
All grades of TRAE in 10% or more of patients include cytokine release syndrome (CRS; 44%; ≥ grade 3, 2%), fever (19%), fatigue (14%), anemia (10%; ≥ grade 3 , 2%) and nausea (10%).
8% of patients had grade 4 or higher AEs, including pneumonia (n = 1) and lymphopenia (n = 3); 1 patient died of pneumonia.
Cytokine release syndrome (CRS) is usually mild and manifests as fever (31%), tachycardia (19%), and nausea (14%).
With supportive therapy, steroids, intravenous fluids, and/or anti-interleukin (IL)-6 therapy, TRAE is usually reversible, and CRS is not related to treatment discontinuation or death.
The researchers also explored the early rise of cytokine levels associated with the occurrence of CRS. All CRS cases occurred in the first treatment cycle; two recurrences were reported in the second and third cycles.
The median time to occurrence of CRS after administration of AMG 757 is 9 hours (range: 3-52 hours); the median duration of CRS is 60 hours (range: 3-197 hours).
AMG757 chose DLL3 as an antibody targeting tumor cells, which has shown preliminary efficacy and acceptable safety in preclinical and phase I clinical studies.
As the dose escalation study progresses, the optimal dose will be determined, and phase II clinical data is expected.
Sum up:
As the most difficult to treat SCLC, it is also expected to usher in the first targeted drug. In addition to AMG757, AMG119, a CAR-T therapy targeting DLL3, is also in phase I clinical studies.
Other bispecific antibodies HPN328 (targeting DLL3, CD3 and albumin) and the preclinical DLL3/CD47 double antibody PT217 have also been studied accordingly.
Hedgehog (Hh) signaling pathway inhibitor
The Hh signaling pathway plays an important role in embryonic development.
Studies have found that the Hh signaling pathway molecule Smo protein can promote the formation of SCLC in mice with mutations in RB1 and Tp53 genes, while reducing Smo can inhibit tumor formation; giving mice Hh signaling pathway inhibitors can reduce the recurrence of SCLC, indicating SCLC is sensitive to Hh signaling pathway inhibitors.
Currently, Hh signaling pathway inhibitor LDE225+etoposide+cisplatin is undergoing phase I clinical trials for the treatment of advanced SCLC.
Summary and outlook
With the in-depth study of the pathological mechanism of SCLC and the development of clinical trials of related targeted therapy drugs, new research directions have been brought to the treatment of SCLC.
It is hoped that these targeted drugs can make breakthroughs in the field of SCLC treatment, enter the clinic as soon as possible, and benefit more SCLC patients.
Why has no targeted drug been approved for Small cell lung cancer so far?
(source:internet, reference only)
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