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*Only for medical professionals to read for reference ADC combination therapy is expected to bring new hope to lung cancer patients! Antibody-drug conjugate (ADC) is a type of targeted biopharmaceutical that couples a target-specific monoclonal antibody with a highly lethal cytotoxic drug through a specific connector.
As a carrier, small-molecule cytotoxic drugs can be efficiently transported to target tumor cells in a targeted manner [1]
.
The concept of ADC drugs was originally derived from the concept of "magic bullet" proposed by Paul Ehrlich 100 years ago, but it was not until the 1980s that there was rapid progress with the development of non-immunogenic (especially humanized) monoclonal antibodies.
.
ADC drugs combine the advantages of targeted, selective antibodies and cytotoxic drugs with high anti-tumor activity.
While retaining the tumor-killing properties of small molecule cytotoxic drugs, it selectively reduces the off-target side effects of small molecule cytotoxic drugs, and is effective Improve the benefit-risk ratio of anti-tumor therapy
.
Therefore, ADC drugs have been one of the hot research directions in the field of tumor precision therapy in recent years [1]
.
Lung cancer is the cancer with the highest morbidity and mortality in the world, and researchers have never stopped exploring its treatment
.
In addition to targeted therapy and immunotherapy, there are more and more ADC therapies related to lung cancer
.
Previous studies have shown that ADC drugs have a certain curative effect in the treatment of refractory non-small cell lung cancer (NSCLC) patients, with an objective response rate (ORR) of 20.
3%~39%[2-3]
.
However, there are still many challenges in the treatment of NSCLC with ADC drugs, such as possible side effects during treatment, no ideal predictive biomarkers, insufficient understanding of the resistance mechanism of ADC drugs at this stage, and how to find a reasonable ADC combination treatment strategies
.
Among them, a reasonable ADC combination therapy strategy has always been the direction that scientists are exploring
.
What is a reasonable ADC combination therapy strategy? A reasonable combination of ADC strategies can increase ADC activity [4], which may be achieved in the following four forms: 1.
Increase the delivery of ADC to tumor tissues: anti-angiogenic drugs, such as drugs that target the VEGF signaling pathway, may promote tumor blood vessels Normalize to improve the delivery of ADC to tumor tissue, or enhance the cytotoxic effect of ADC (Figure 1a)
.
2.
Regulation of antibody target protein expression and/or process: drugs that increase the expression of target antigens on the surface of tumor cells may promote the binding of antibody antigens
.
In addition, drugs that enhance antigen conversion or degradation may promote ADC uptake and payload cleavage and release, thereby enhancing cytotoxicity (Figure 1b)
.
3.
Enhance payload activity and/or synthetic lethality: other drugs that play a synergistic effect through complementary mechanisms or synthetic lethality can enhance payload activity (Figure 1c)
.
4.
Promote anti-tumor immunity: immunotherapy has the potential to build on anti-tumor immunity induced by ADCs, which can be achieved by enhancing antibody-dependent cellular cytotoxicity or by enhancing cell-mediated tumor recognition and immune effect functions (Figure 1d)
.
Figure 1.
Reasonable combination therapy strategies to improve ADC activity.
In recent years, what new developments have been made in ADC combination therapy for NSCLC? 01ADC and anti-angiogenesis drug joint research is underway The results of the extended cohort study (NCT02187848) showed that [5], SAR408701 has good anti-tumor activity in advanced non-squamous NSCLC patients with high CEACAM5 expression who have previously received multiple lines of treatment
.
As of January 2020, a total of 92 patients were enrolled in the study, including 28 patients with moderate CEACAM5 expression (1% to 49%) and 64 patients with high CEACAM5 expression (≥50%)
.
Analyzing the primary endpoint ORR, in patients with high CEACAM5 expression, ORR reached 20.
3% (13 cases achieved partial remission) (Figure 2)
.
Figure 2.
The ORR results of the CEACAM5 high expression cohort are based on the promising anti-tumor activity of SAR408701 in patients with advanced non-squamous NSCLC with high CEACAM5 expression who have received multiple lines of treatment.
SAR408701 combined with ramoxicumumab A phase II study of combination therapy for previously treated non-squamous NSCLC is ongoing (Table 1)
.
Table 1.
NCT04394624 Study 02 Irreversible pan-HER inhibitors can enhance T-DM1 activity.
To determine whether the enhancement of receptor internalization caused by the combination of neratinib and T-DM1 can enhance the anti-tumor efficacy, this preclinical study adopted Nelatinib, T-DM1 or combination treatment of the same lung human tumor xenograft models (PDXs) with ERBB2 amplification and mutation (S310F)
.
The results showed that although the combination of T-DM1 and T-DM1 with neratinib can induce significant tumor regression, the combination therapy has a longer-lasting effect (although the activity observed with neratinib monotherapy can be ignored) [ 6] (Picture 3)
.
Figure 3.
Nelatinib can enhance the efficacy of T-DM1.
Another study is consistent with the above-mentioned preclinical data.
In this study, a 41-year-old ERBB2 amplified breast cancer patient with lung metastasis was receiving multiple anti-HER2 treatments.
Relapse later (including T-DM1)
.
Nelatinib was added to T-DM1 immediately after T-DM1 progressed, and the patient had an active partial response (-38%) after 6 weeks of treatment [6] (Figure 4)
.
Figure 4.
Nelatinib can enhance the efficacy of T-DM1.
There is a potential synergy between 03ADC and immune checkpoint inhibitor (ICI).
Studies have shown that Trastuzumab Deruxtecan (T-Dxd) can enhance the anti-tumor effect of syngeneic mouse models.
Immune function [7-8]: 1.
Up-regulate CD862 on dendritic cells (DCs).
Increase tumor-infiltrating DCs/CD8+ T cells 3.
Up-regulate the expression of programmed death ligand 1 (PD-L1) 4.
And programmed Death ligand (PD-1) monoclonal antibody has anti-tumor synergistic effects.
Figure 5.
There is a potential synergy between ADC and ICI.
A single-arm, multi-center trial involving 54 cases of previously treated metastatic non-small cells Patients with lung cancer received 8 or 10 mg/kg sacituzumab govitecan (IMMU-132) (a Trop-2 ADC targeting SN-38) on the 1st and 8th day of the 21-day cycle
.
In the response assessment study population (n = 47), the ORR was 19%; the average response time was 6 months (95% CI, 4.
8-8.
3 months); the median progression-free survival of the intent-to-treat (ITT) population was At 5.
2 months (95% CI, 3.
2-7.
1 months), the median overall survival of the ITT population was 9.
5 months (95% CI, 5.
9-16.
7 months) (Figure 6) [9]
.
Figure 6.
The results of sacituzumab govitecan in the treatment of previously treated NSCLC based on the results of this study, a phase Ib/II, open-label, multi-center, random umbrella study of atelizumab combined with atelizumab is underway (Figure 7) [10]
.
Figure 7.
Morpheus-Lung study design.
A number of ADC combination treatment studies are currently underway (Table 2) [11].
In the future, we look forward to more ADC combination programs for the clinical treatment of NSCLC patients.
I hope that the ADC combination treatment program will soon become New treatment options for patients with lung cancer
.
Table 2.
Ongoing ADC combination therapy research references: [1].
Expert consensus on the clinical application of antibody-drug conjugates in the treatment of malignant tumors (2020 edition) [J].
Chinese Journal of Oncology, 2021,01:78-91.
[ 2].
Nakagawa.
WCLC 2020; Jänne PA.
ASCO 2021.
[3].
Camidge DR.
AACR 2021; GazzahA.
ASCO 2020.
[4].
Joshua Z Drago, Shanu Modi, Sarat Chandarlapaty.
Unlocking the potential of antibody-drug conjugates for cancer therapy.
Nat Rev Clin Oncol.
2021 Jun;18(6)327-344[5].
Gazzah A,Ricordel C,Cousin S,et al.
Efficacy and safety of the antibody-drug conjugate(ADC) SAR408701 in patients(pts) with non-squamous non-small cell lung cancer(NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5(CEACAM5) [EB/OL].
J Clin Oncol 38:2020(suppl;Abstr 9505).
[ 6].
Bob T Li, Flavia Michelini, Sandra Misale et al.
HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers.
Cancer Discov.
2020 May;10(5)674-687.
[7].
Nakayama T .
Mol Cancer Ther 2018[8].
Gajewski TF.
Nature Immunol 2013[9].
Heist RS, Guarino MJ,et al.
Therapy of Advanced Non-Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate , Sacituzumab Govitecan.
J Clin Oncol.
2017 May 26[10].
https:// ClinicalTrials.
gov*This article It is only used to provide scientific information to medical professionals and does not represent the views of this platform
As a carrier, small-molecule cytotoxic drugs can be efficiently transported to target tumor cells in a targeted manner [1]
.
The concept of ADC drugs was originally derived from the concept of "magic bullet" proposed by Paul Ehrlich 100 years ago, but it was not until the 1980s that there was rapid progress with the development of non-immunogenic (especially humanized) monoclonal antibodies.
.
ADC drugs combine the advantages of targeted, selective antibodies and cytotoxic drugs with high anti-tumor activity.
While retaining the tumor-killing properties of small molecule cytotoxic drugs, it selectively reduces the off-target side effects of small molecule cytotoxic drugs, and is effective Improve the benefit-risk ratio of anti-tumor therapy
.
Therefore, ADC drugs have been one of the hot research directions in the field of tumor precision therapy in recent years [1]
.
Lung cancer is the cancer with the highest morbidity and mortality in the world, and researchers have never stopped exploring its treatment
.
In addition to targeted therapy and immunotherapy, there are more and more ADC therapies related to lung cancer
.
Previous studies have shown that ADC drugs have a certain curative effect in the treatment of refractory non-small cell lung cancer (NSCLC) patients, with an objective response rate (ORR) of 20.
3%~39%[2-3]
.
However, there are still many challenges in the treatment of NSCLC with ADC drugs, such as possible side effects during treatment, no ideal predictive biomarkers, insufficient understanding of the resistance mechanism of ADC drugs at this stage, and how to find a reasonable ADC combination treatment strategies
.
Among them, a reasonable ADC combination therapy strategy has always been the direction that scientists are exploring
.
What is a reasonable ADC combination therapy strategy? A reasonable combination of ADC strategies can increase ADC activity [4], which may be achieved in the following four forms: 1.
Increase the delivery of ADC to tumor tissues: anti-angiogenic drugs, such as drugs that target the VEGF signaling pathway, may promote tumor blood vessels Normalize to improve the delivery of ADC to tumor tissue, or enhance the cytotoxic effect of ADC (Figure 1a)
.
2.
Regulation of antibody target protein expression and/or process: drugs that increase the expression of target antigens on the surface of tumor cells may promote the binding of antibody antigens
.
In addition, drugs that enhance antigen conversion or degradation may promote ADC uptake and payload cleavage and release, thereby enhancing cytotoxicity (Figure 1b)
.
3.
Enhance payload activity and/or synthetic lethality: other drugs that play a synergistic effect through complementary mechanisms or synthetic lethality can enhance payload activity (Figure 1c)
.
4.
Promote anti-tumor immunity: immunotherapy has the potential to build on anti-tumor immunity induced by ADCs, which can be achieved by enhancing antibody-dependent cellular cytotoxicity or by enhancing cell-mediated tumor recognition and immune effect functions (Figure 1d)
.
Figure 1.
Reasonable combination therapy strategies to improve ADC activity.
In recent years, what new developments have been made in ADC combination therapy for NSCLC? 01ADC and anti-angiogenesis drug joint research is underway The results of the extended cohort study (NCT02187848) showed that [5], SAR408701 has good anti-tumor activity in advanced non-squamous NSCLC patients with high CEACAM5 expression who have previously received multiple lines of treatment
.
As of January 2020, a total of 92 patients were enrolled in the study, including 28 patients with moderate CEACAM5 expression (1% to 49%) and 64 patients with high CEACAM5 expression (≥50%)
.
Analyzing the primary endpoint ORR, in patients with high CEACAM5 expression, ORR reached 20.
3% (13 cases achieved partial remission) (Figure 2)
.
Figure 2.
The ORR results of the CEACAM5 high expression cohort are based on the promising anti-tumor activity of SAR408701 in patients with advanced non-squamous NSCLC with high CEACAM5 expression who have received multiple lines of treatment.
SAR408701 combined with ramoxicumumab A phase II study of combination therapy for previously treated non-squamous NSCLC is ongoing (Table 1)
.
Table 1.
NCT04394624 Study 02 Irreversible pan-HER inhibitors can enhance T-DM1 activity.
To determine whether the enhancement of receptor internalization caused by the combination of neratinib and T-DM1 can enhance the anti-tumor efficacy, this preclinical study adopted Nelatinib, T-DM1 or combination treatment of the same lung human tumor xenograft models (PDXs) with ERBB2 amplification and mutation (S310F)
.
The results showed that although the combination of T-DM1 and T-DM1 with neratinib can induce significant tumor regression, the combination therapy has a longer-lasting effect (although the activity observed with neratinib monotherapy can be ignored) [ 6] (Picture 3)
.
Figure 3.
Nelatinib can enhance the efficacy of T-DM1.
Another study is consistent with the above-mentioned preclinical data.
In this study, a 41-year-old ERBB2 amplified breast cancer patient with lung metastasis was receiving multiple anti-HER2 treatments.
Relapse later (including T-DM1)
.
Nelatinib was added to T-DM1 immediately after T-DM1 progressed, and the patient had an active partial response (-38%) after 6 weeks of treatment [6] (Figure 4)
.
Figure 4.
Nelatinib can enhance the efficacy of T-DM1.
There is a potential synergy between 03ADC and immune checkpoint inhibitor (ICI).
Studies have shown that Trastuzumab Deruxtecan (T-Dxd) can enhance the anti-tumor effect of syngeneic mouse models.
Immune function [7-8]: 1.
Up-regulate CD862 on dendritic cells (DCs).
Increase tumor-infiltrating DCs/CD8+ T cells 3.
Up-regulate the expression of programmed death ligand 1 (PD-L1) 4.
And programmed Death ligand (PD-1) monoclonal antibody has anti-tumor synergistic effects.
Figure 5.
There is a potential synergy between ADC and ICI.
A single-arm, multi-center trial involving 54 cases of previously treated metastatic non-small cells Patients with lung cancer received 8 or 10 mg/kg sacituzumab govitecan (IMMU-132) (a Trop-2 ADC targeting SN-38) on the 1st and 8th day of the 21-day cycle
.
In the response assessment study population (n = 47), the ORR was 19%; the average response time was 6 months (95% CI, 4.
8-8.
3 months); the median progression-free survival of the intent-to-treat (ITT) population was At 5.
2 months (95% CI, 3.
2-7.
1 months), the median overall survival of the ITT population was 9.
5 months (95% CI, 5.
9-16.
7 months) (Figure 6) [9]
.
Figure 6.
The results of sacituzumab govitecan in the treatment of previously treated NSCLC based on the results of this study, a phase Ib/II, open-label, multi-center, random umbrella study of atelizumab combined with atelizumab is underway (Figure 7) [10]
.
Figure 7.
Morpheus-Lung study design.
A number of ADC combination treatment studies are currently underway (Table 2) [11].
In the future, we look forward to more ADC combination programs for the clinical treatment of NSCLC patients.
I hope that the ADC combination treatment program will soon become New treatment options for patients with lung cancer
.
Table 2.
Ongoing ADC combination therapy research references: [1].
Expert consensus on the clinical application of antibody-drug conjugates in the treatment of malignant tumors (2020 edition) [J].
Chinese Journal of Oncology, 2021,01:78-91.
[ 2].
Nakagawa.
WCLC 2020; Jänne PA.
ASCO 2021.
[3].
Camidge DR.
AACR 2021; GazzahA.
ASCO 2020.
[4].
Joshua Z Drago, Shanu Modi, Sarat Chandarlapaty.
Unlocking the potential of antibody-drug conjugates for cancer therapy.
Nat Rev Clin Oncol.
2021 Jun;18(6)327-344[5].
Gazzah A,Ricordel C,Cousin S,et al.
Efficacy and safety of the antibody-drug conjugate(ADC) SAR408701 in patients(pts) with non-squamous non-small cell lung cancer(NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5(CEACAM5) [EB/OL].
J Clin Oncol 38:2020(suppl;Abstr 9505).
[ 6].
Bob T Li, Flavia Michelini, Sandra Misale et al.
HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers.
Cancer Discov.
2020 May;10(5)674-687.
[7].
Nakayama T .
Mol Cancer Ther 2018[8].
Gajewski TF.
Nature Immunol 2013[9].
Heist RS, Guarino MJ,et al.
Therapy of Advanced Non-Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate , Sacituzumab Govitecan.
J Clin Oncol.
2017 May 26[10].
https:// ClinicalTrials.
gov*This article It is only used to provide scientific information to medical professionals and does not represent the views of this platform
