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Loratinib is the third-generation AKL-TKI, which has a good ability to pass through the blood-brain barrier.
In the CROWN study, loratinib showed good efficacy in the first-line treatment of ALK-positive advanced non-small cell lung cancer (NSCLC) patients.
Recently, researchers announced the results of a multi-cohort study aimed at exploring the efficacy and safety of loratinib in the treatment of advanced NSCLC patients who have progressed through the second-generation ALK-TKI treatment.
Study results recently published in the journal Annals of Oncology Author: Medical benevolence author authorization issued NMT Medical, please do not reprint without authorization.
Research background Although the second-generation ALK-TKI is widely used, brain metastasis is still the main reason for the failure of patients to receive TKI drugs.
Loratinib is a third-generation ALK-TKI drug that has a good ability to pass through the blood-brain barrier and has a blocking effect on a variety of ALK resistance mutations.
In a phase I/II clinical study, loratinib has achieved good results in the treatment of advanced NSCLC patients who have previously received ALK-TKI treatment.
At the first data analysis, the overall objective response rate (ORR) was 32%.
Even for patients who had been treated with more than two ALK-TKI in the past, the ORR still reached 39%, and the response time was durable.
Based on the data from this study, loratinib is approved for use in patients with advanced NSCLC who have previously been treated with aletinib or ceritinib.
This study aims to update the intracranial and extracranial efficacy data after follow-up.
Research methods This phase I/II clinical study included patients with ALK-positive advanced NSCLC confirmed by histopathology or cytopathology, with a PS score of 0-2, age ≥18 years, and patients with asymptomatic brain metastases were allowed to enter the group.
Patients who had undergone a second-generation ALK-TKI treatment comprised cohort 3b; patients who had undergone two or three ALK-TKI treatments in the past comprised cohorts 4 and 5.
Regardless of whether the patient has received chemotherapy in the past, all patients are allowed to join the group.
The therapeutic dose of loratinib is 100 mg (orally, once a day), and the treatment is continued until the disease progresses, an intolerable toxic reaction occurs, or the patient withdraws the informed consent.
Efficacy evaluations were conducted every 6 weeks for the first 30 months, and then every 12 weeks.
The primary study endpoint was ORR, and the secondary study endpoints were duration of remission (DoR), progression-free survival (PFS), overall survival (OS), and safety.
During the data analysis, the data of cohort 4 and cohort 5 were merged, because for this part of patients, no standard ALK-TKI drugs are currently available.
Results of the study: A total of 139 patients were enrolled in this study, of which 28 patients had previously received only one second-generation ALK-TKI treatment (cohort 3b), and 111 patients had previously received at least two or more ALK-TKI treatments (ie, cohort 4 and 5).
In the whole group of patients, 68.
3% had brain metastases at baseline, and the proportions of patients who received aletinib or ceritinib as the last ALK-TKI treatment were 44.
6% and 33.
8%, respectively.
Among the 139 patients who had previously received at least one second-generation ALK-TKI treatment, the overall ORR was 39.
6% (Figure 1), the DoR was 9.
6 months, and the median PFS was 6.
6 months, in 59% of patients At the time of death, the median OS was 20.
7 months.
Figure 1 ORR of the whole group of patients.
Among the patients who have been treated with a second-generation ALK-TKI, the ORR was 42.
9% (1 CR, 11 PR), the median DoR was 6.
2 months, and the median PFS was 5.
5 Months, the median OS was 38.
5 months (data maturity 46.
4%). Among patients who had received at least two ALK-TKI treatments in the past, the ORR was 38.
7% (2 CR, 41 PR), the median DoR was 9.
9 months, the median PFS was 6.
9 months, and the median OS was 19.
2 Months (data maturity 62.
2%).
In the whole group of patients, the ORR of patients who had received chemotherapy was 43%, and the ORR of patients who had not received chemotherapy was 32.
6%.
In the whole group of patients, 57 patients (41%) had measurable brain metastases at baseline, intracranial ORR was 56.
1% (12 CR, 20 PR) (Figure 2), and median intracranial DoR was 12.
4 months .
Figure 2 The intracranial ORR extracranial ORR was 36.
7% (5 CR, 46 PR) (Figure 3), and the median extracranial DoR was 9.
7 months.
In patients who had received only one second-generation ALK-TKI treatment in the past, the intracranial ORR was 66.
7%, the extracranial ORR was 32.
1%, and the median DoR was 20.
7 months and not reached, respectively.
Of 111 patients who had previously undergone two ALK-TKI treatments, 48 patients had measurable brain metastases.
The intracranial ORR was 54.
2%, and the extracranial ORR was 37.
8%.
The median DoR was 12.
4 months and 7.
1 months, respectively.
Figure 3 Further analysis of extracranial ORR found that patients who completed craniocerebral radiotherapy 8 to 12 weeks before treatment did not affect the intracranial efficacy of loratinib.
40.
3%, 37.
5%, and 40.
4% of patients received aletinib, brigatinib, and ceritinib in the last treatment, respectively.
The intracranial ORR was 40.
5%, 40%, and 55.
6%, respectively.
Safety: There were no new adverse events in the study.
The most common adverse events of any grade were hypercholesterolemia 84.
4%, hypertriglyceridemia 67.
1%, edema 45.
8%, peripheral neuropathy 34.
2%, cognition 23.
7% of abnormalities, 23.
7% of weight gain, 15.
6% of abnormal moods, and 10.
2% of fatigue. Dose reduction occurred in 25.
4% of patients, treatment was temporarily interrupted in 81.
7% of patients, and treatment was discontinued in 3.
4% of patients due to treatment-related adverse events.
Research conclusions For NSCLC patients treated with second-generation ALK-TKI, loratinib still has good intracranial and extracranial curative effects.
Reference: E Felip et al.
Ann Oncol.
2021 Feb 24; S0923-7534(21)00129-0.
DOI: 10.
1016/j.
annonc.
2021.
02.
012.
https://pubmed.
ncbi.
nlm.
nih.
gov /33639216/
In the CROWN study, loratinib showed good efficacy in the first-line treatment of ALK-positive advanced non-small cell lung cancer (NSCLC) patients.
Recently, researchers announced the results of a multi-cohort study aimed at exploring the efficacy and safety of loratinib in the treatment of advanced NSCLC patients who have progressed through the second-generation ALK-TKI treatment.
Study results recently published in the journal Annals of Oncology Author: Medical benevolence author authorization issued NMT Medical, please do not reprint without authorization.
Research background Although the second-generation ALK-TKI is widely used, brain metastasis is still the main reason for the failure of patients to receive TKI drugs.
Loratinib is a third-generation ALK-TKI drug that has a good ability to pass through the blood-brain barrier and has a blocking effect on a variety of ALK resistance mutations.
In a phase I/II clinical study, loratinib has achieved good results in the treatment of advanced NSCLC patients who have previously received ALK-TKI treatment.
At the first data analysis, the overall objective response rate (ORR) was 32%.
Even for patients who had been treated with more than two ALK-TKI in the past, the ORR still reached 39%, and the response time was durable.
Based on the data from this study, loratinib is approved for use in patients with advanced NSCLC who have previously been treated with aletinib or ceritinib.
This study aims to update the intracranial and extracranial efficacy data after follow-up.
Research methods This phase I/II clinical study included patients with ALK-positive advanced NSCLC confirmed by histopathology or cytopathology, with a PS score of 0-2, age ≥18 years, and patients with asymptomatic brain metastases were allowed to enter the group.
Patients who had undergone a second-generation ALK-TKI treatment comprised cohort 3b; patients who had undergone two or three ALK-TKI treatments in the past comprised cohorts 4 and 5.
Regardless of whether the patient has received chemotherapy in the past, all patients are allowed to join the group.
The therapeutic dose of loratinib is 100 mg (orally, once a day), and the treatment is continued until the disease progresses, an intolerable toxic reaction occurs, or the patient withdraws the informed consent.
Efficacy evaluations were conducted every 6 weeks for the first 30 months, and then every 12 weeks.
The primary study endpoint was ORR, and the secondary study endpoints were duration of remission (DoR), progression-free survival (PFS), overall survival (OS), and safety.
During the data analysis, the data of cohort 4 and cohort 5 were merged, because for this part of patients, no standard ALK-TKI drugs are currently available.
Results of the study: A total of 139 patients were enrolled in this study, of which 28 patients had previously received only one second-generation ALK-TKI treatment (cohort 3b), and 111 patients had previously received at least two or more ALK-TKI treatments (ie, cohort 4 and 5).
In the whole group of patients, 68.
3% had brain metastases at baseline, and the proportions of patients who received aletinib or ceritinib as the last ALK-TKI treatment were 44.
6% and 33.
8%, respectively.
Among the 139 patients who had previously received at least one second-generation ALK-TKI treatment, the overall ORR was 39.
6% (Figure 1), the DoR was 9.
6 months, and the median PFS was 6.
6 months, in 59% of patients At the time of death, the median OS was 20.
7 months.
Figure 1 ORR of the whole group of patients.
Among the patients who have been treated with a second-generation ALK-TKI, the ORR was 42.
9% (1 CR, 11 PR), the median DoR was 6.
2 months, and the median PFS was 5.
5 Months, the median OS was 38.
5 months (data maturity 46.
4%). Among patients who had received at least two ALK-TKI treatments in the past, the ORR was 38.
7% (2 CR, 41 PR), the median DoR was 9.
9 months, the median PFS was 6.
9 months, and the median OS was 19.
2 Months (data maturity 62.
2%).
In the whole group of patients, the ORR of patients who had received chemotherapy was 43%, and the ORR of patients who had not received chemotherapy was 32.
6%.
In the whole group of patients, 57 patients (41%) had measurable brain metastases at baseline, intracranial ORR was 56.
1% (12 CR, 20 PR) (Figure 2), and median intracranial DoR was 12.
4 months .
Figure 2 The intracranial ORR extracranial ORR was 36.
7% (5 CR, 46 PR) (Figure 3), and the median extracranial DoR was 9.
7 months.
In patients who had received only one second-generation ALK-TKI treatment in the past, the intracranial ORR was 66.
7%, the extracranial ORR was 32.
1%, and the median DoR was 20.
7 months and not reached, respectively.
Of 111 patients who had previously undergone two ALK-TKI treatments, 48 patients had measurable brain metastases.
The intracranial ORR was 54.
2%, and the extracranial ORR was 37.
8%.
The median DoR was 12.
4 months and 7.
1 months, respectively.
Figure 3 Further analysis of extracranial ORR found that patients who completed craniocerebral radiotherapy 8 to 12 weeks before treatment did not affect the intracranial efficacy of loratinib.
40.
3%, 37.
5%, and 40.
4% of patients received aletinib, brigatinib, and ceritinib in the last treatment, respectively.
The intracranial ORR was 40.
5%, 40%, and 55.
6%, respectively.
Safety: There were no new adverse events in the study.
The most common adverse events of any grade were hypercholesterolemia 84.
4%, hypertriglyceridemia 67.
1%, edema 45.
8%, peripheral neuropathy 34.
2%, cognition 23.
7% of abnormalities, 23.
7% of weight gain, 15.
6% of abnormal moods, and 10.
2% of fatigue. Dose reduction occurred in 25.
4% of patients, treatment was temporarily interrupted in 81.
7% of patients, and treatment was discontinued in 3.
4% of patients due to treatment-related adverse events.
Research conclusions For NSCLC patients treated with second-generation ALK-TKI, loratinib still has good intracranial and extracranial curative effects.
Reference: E Felip et al.
Ann Oncol.
2021 Feb 24; S0923-7534(21)00129-0.
DOI: 10.
1016/j.
annonc.
2021.
02.
012.
https://pubmed.
ncbi.
nlm.
nih.
gov /33639216/
