Gefitinib(geftinat)印度版 吉非替尼

[Indications of Gefitinib(geftinat)]

Gefitinib(geftinat) is suitable for locally advanced or metastatic non-small cell lung cancer that has received chemotherapy (platinum and docetaxel).

[Gefitinib(geftinat) Specification]

This product is a tablet with the specification of 250mg/30 tablets.

[Gefitinib(geftinat) Administration Method]

The recommended dosage is 250mg(1 tablet) once a day.

[Notes for Gefitinib(geftinat)]

Phase II clinical study

Two large-scale phase II clinical studies evaluated the efficacy and safety of this drug as a monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). The score of the patient’s WHO physical condition is 0-2, and he must be a failure of previous chemotherapy:

* IDEAL 1 (study 0016), who had received one or two chemotherapy regimens in the past, and at least one of them included platinum therapy (median age was 59.6 years [28-85 years]; n=209）

* IDEAL 2 (study 0039), who received two or more chemotherapy regimens in the past, including platinum and docetaxel at the same time or successively (median age is 61 years old [30-84 years old]; n=216）

The two studies were similar in design, both were double-blind, parallel groups and multicenter. Two oral doses of gefitinib were evaluated: 250mg/ day and 500mg/ day. Patients were randomly assigned to these two dose groups. In IDEAL 1, the primary end point is the objective remission rate of tumor, and the secondary end point is the improvement of disease-related symptoms; In IDEAL 2, the main end points are the objective remission rate of tumor and the improvement rate of disease-related symptoms (measured by LCS every week).

Phase III clinical study

In a double-blind, placebo-controlled, parallel-grouped phase III clinical study, this product was compared with placebo in patients with advanced non-small cell lung cancer who had previously received one or two chemotherapy regimens. The primary outcome measure was overall survival, and the secondary outcomes included time to treatment failure, objective remission and QoL. Another exploratory goal is the status of EGFR and other related biomarkers, including the relationship between EGFR expression and EGFR mutation status and therapeutic effect.

Curative effect result

Phase II clinical study

See the table below for a summary of the therapeutic results of IDEAL1 and IDEAL2. Regardless of the WHO physical condition score (0, 1 or 2) and the number of chemotherapy received in the past, the objective remission rate of tumors obtained in the two studies is similar. The objective remission of most patients occurred in the first month of treatment, and the objective remission of a small number of patients could occur as late as the fourth month of treatment.

A In the IDEAL1 trial, whether it is 250mg or 500mg, the objective remission rate of Japanese patients is higher than that of non-Japanese patients (250mg is 27.5%: 9.6% and 500mg is 27.5%: 11.1%).

+Data continues as of the deadline.

PFS survives without progress.

Phase III clinical study

In the general population or in the subgroup of patients with adenocarcinoma, this product did not significantly prolong the survival time (in the general population: HR 0.89, CI 0.77 to 1.02, p=0.09, the median survival time of this product was 5.6 months, and that of placebo was 5.1 months; In adenocarcinoma subgroup: HR 0.84, CI 0.68 to 1.03, p=0.09, the median survival time of this product was 6.3 months, and that of placebo was 5.4 months). For the improvement of quality of life and symptoms, this product has not shown any obvious benefit. Pre-set subgroup analysis showed that compared with placebo, this product significantly prolonged the survival of patients in the oriental population and those who had never smoked (in the oriental population: HR = 0.66, CI 0.48 to 0.91, p=0.01, the median survival time of this product was 9.5 months, and that of placebo was 5.5 months; Among patients who have never smoked: HR = 0.67, CI 0.49 to 0.92, p=0.01, the median survival time of this product is 8.9 months, and that of placebo is 6.1 months).

The data analysis of EGFR gene replication number showed that compared with placebo, the survival of patients with high EGFR gene replication number was longer than that of patients with low EGFR gene replication number (interaction P value = 0.0448). The mortality risk ratio (HR) of this product to placebo was 0.61 (n = 114; The 95% CI was 0.36-1.04, P = 0.067), while the patient group with low EGFR gene replication was 1.16 (n = 256; 95％CI 0.81-1.64，p＝0.42）。 For patients whose EGFR gene replication number was not detected (n = 1322; HR＝0.85； CI 0.73-0.99, p = 0.032), which is as expected, and the hazard ratio is similar to that of the total research population. The replication number of EGFR gene was analyzed by fluorescence in situ hybridization (FISH), that is, LSI EGFR spectrum orange/CEP 7 spectrum green probe was used. If a patient’s tumor has high pleomorphism (replication of ≥4 in ≥ 40% cells) or gene amplification (dense EGFR gene groups and gene/chromosome ratio of ≥2 in each cell, or EGFR replication of ≥15 in ≥10% cells analyzed), it is considered that the patient’s EGFR gene replication is high.

The analysis of EGFR protein expression data showed that when treated with this product, compared with placebo (N=264, HR=0.77, CI 0.56-1.08, p=0.13), patients with EGFR-positive tumors had better survival results than patients with EGFR-negative tumors (N=115, HR=1.57, CI 0.86-2.87, P = For the patients whose EGFR expression was not detected (n = 1313; HR＝0.84； CI 0.73-0.98, p = 0.03), which is as expected, and the hazard ratio is similar to that of the total research population. The definition of positive EGFR expression status is that at least 10% of cells have detected EGFR in staining, while the difference standard listed in the instructions of DAKO EGFR pharmDx reagent is 1%.

The analysis of EGFR gene mutation data shows that patients with EGFR mutation have higher remission rate than patients without EGFR mutation, and tend to be women, non-smokers or people with adenocarcinoma tissue. However, there is not enough data to make a meaningful survival evaluation.

security

The safety of this product is similar in all studies, and the incidence and severity of adverse events are dose-related (see adverse reactions).

conclusion

Clinical research data prove that some patients with locally advanced or metastatic non-small cell lung cancer can achieve sustained and objective remission with this product. In phase III clinical studies, this product did not prolong the survival time in the general population or in patients with adenocarcinoma subgroup. The patients who are most likely to benefit from this product are patients from the eastern population, patients who have never smoked, or patients with high EGFR gene replication. Patients with low EGFR gene replication or negative EGFR expression are unlikely to benefit from the treatment of this product.

Clinical research in China.

Clinical studies were conducted in five clinical research bases in China to evaluate the objective remission rate of gefitinib tablets 250mg/ day in patients with non-small cell lung cancer who had previously received chemotherapy.

A total of 159 subjects took gefitinib tablets 250mg at least once. The demographic and disease characteristics of the subjects are shown in Table 2. Among them, 75 (47.2%) had received one chemotherapy regimen before enrollment, and 50 (31.4%) and 34 (21.4%) had received two or more chemotherapy regimens respectively. The validity of 159 subjects (intentional treatment population) was analyzed.

Table 3 summarizes the curative effect. There are some differences in the objective remission rates in different treatment subgroups (according to the baseline characteristics at the time of enrollment, the objective remission rates of subjects are shown in Table 4), and similar differences are also found in other international multi-center clinical studies. Although the number of subjects in some subgroups is not enough, the effect of gefitinib on these subjects is consistent with the expectation.