Xalkori (Page 6 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with crizotinib have not been conducted.

Crizotinib was genotoxic in an in vitro micronucleus assay in Chinese Hamster Ovary cultures, in an in vitro human lymphocyte chromosome aberration assay, and in in vivo rat bone marrow micronucleus assays. Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.

No specific studies with crizotinib have been conducted in animals to evaluate the effect on fertility; however, crizotinib is considered to have the potential to impair reproductive function and fertility in humans based on findings in repeat-dose toxicity studies in the rat. Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given greater than or equal to 50 mg/kg/day for 28 days (greater than 1.7 times the recommended human dose based on AUC). Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 500 mg/kg/day (approximately 10 times the recommended human dose based on body surface area) for 3 days.

14 CLINICAL STUDIES

14.1 ALK- or ROS1-Positive Metastatic Non-Small Cell Lung Cancer

Previously Untreated ALK-Positive Metastatic NSCLC — Study 1 (PROFILE 1014; NCT01154140)

The efficacy of XALKORI for the treatment of patients with ALK-positive metastatic NSCLC, who had not received previous systemic treatment for advanced disease, was demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 1). Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit, prior to randomization. The major efficacy outcome measure was progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by independent radiology review (IRR) committee. Additional efficacy outcome measures included objective response rate (ORR) as assessed by IRR, DOR, and overall survival (OS). Patient-reported lung cancer symptoms were assessed at baseline and periodically during treatment.

Patients were randomized to receive XALKORI (n=172) or chemotherapy (n=171). Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0–1, 2), race (Asian, non-Asian), and brain metastases (present, absent). Patients in the XALKORI arm received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Chemotherapy consisted of pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 or carboplatin AUC of 5 or 6 mg×min/mL by intravenous infusion every 3 weeks for up to 6 cycles. Patients in the chemotherapy arm were not permitted to receive maintenance chemotherapy. At the time of documented disease progression, as per independent radiology review, patients randomized to chemotherapy were offered XALKORI.

The demographic characteristics of the overall study population were 62% female, median age of 53 years, baseline ECOG performance status 0 or 1 (95%), 51% White and 46% Asian, 4% current smokers, 32% past smokers, and 64% never smokers. The disease characteristics of the overall study population were metastatic disease in 98% of patients, 92% of patients’ tumors were classified as adenocarcinoma histology, 27% of patients had brain metastases, and 7% received systemic chemotherapy as adjuvant or neoadjuvant therapy. At the time of the final analysis of overall survival, 84% of patients randomized to the chemotherapy arm subsequently received XALKORI.

Study 1 demonstrated a statistically significant improvement in PFS in patients treated with XALKORI. There was no statistically significant difference in OS between patients treated with XALKORI and patients treated with chemotherapy. Table 15 and Figure 1 summarize the efficacy results. Exploratory patient-reported symptom measures of baseline and post-treatment dyspnea, cough, and chest pain suggested a delay in time to development of or worsening of dyspnea, but not cough or chest pain, in patients treated with XALKORI as compared to chemotherapy. The patient-reported delay in onset or worsening of dyspnea may be an overestimation, because patients were not blinded to treatment assignment.

Table 15 Previously Untreated ALK-Positive Metastatic NSCLC — Efficacy Results in Study 1
XALKORI (N=172) Chemotherapy (N=171)
HR=hazard ratio; CI=confidence interval; IRR=independent radiology review; NR=not reached; CR=complete response; PR=partial response.
*
Based on the Cox proportional hazards stratified analysis.
Based on the stratified log-rank test.
Based on the stratified Cochran-Mantel-Haenszel test.

Progression-Free Survival (Based on IRR)

Number of Events (%)

100 (58%)

137 (80%)

Progressive Disease

89 (52%)

132 (77%)

Death

11 (6%)

5 (3%)

Median, Months (95% CI)

10.9 (8.3, 13.9)

7.0 (6.8, 8.2)

HR (95% CI)*

0.45 (0.35, 0.60)

p-value

<0.001

Overall Survival

Number of Events (%)

71 (41%)

81 (47%)

Median, Months (95% CI)

NR (45.8, NR)

47.5 (32.2, NR)

HR (95% CI)*

0.76 (0.55, 1.05)

p-value

0.098

Tumor Responses (Based on IRR)

Objective Response Rate % (95% CI)

74% (67, 81)

45% (37, 53)

CR, n (%)

3 (1.7%)

2 (1.2%)

PR, n (%)

125 (73%)

75 (44%)

p-value

<0.001

Duration of Response

Median, Months (95% CI)

11.3 (8.1, 13.8)

5.3 (4.1, 5.8)

Figure 1. Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR in Study 1

Figure 1
(click image for full-size original)

Previously Treated ALK-Positive Metastatic NSCLC — Study 2 (PROFILE 1007; NCT00932893)

The efficacy of XALKORI as monotherapy for the treatment of 347 patients with ALK-positive metastatic NSCLC, previously treated with 1 platinum-based chemotherapy regimen, were demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 2). The major efficacy outcome was PFS according to RECIST version 1.1 as assessed by IRR. Additional efficacy outcomes included ORR as assessed by IRR, DOR, and OS.

Patients were randomized to receive XALKORI 250 mg orally twice daily (n=173) or chemotherapy (n=174). Chemotherapy consisted of pemetrexed 500 mg/m2 (if pemetrexed-naïve; n=99) or docetaxel 75 mg/m2 (n=72) intravenously (IV) every 21 days. Patients in both treatment arms continued treatment until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Randomization was stratified by ECOG performance status (0–1, 2), brain metastases (present, absent), and prior EGFR tyrosine kinase inhibitor treatment (yes, no). Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart FISH Probe Kit, prior to randomization.

The demographic characteristics of the overall study population were 56% female, median age of 50 years, baseline ECOG performance status 0 or 1 (90%), 52% White and 45% Asian, 4% current smokers, 33% past smokers, and 63% never smokers. The disease characteristics of the overall study population were metastatic disease in at least 95% of patients and at least 93% of patients’ tumors were classified as adenocarcinoma histology. At the time of the final analysis of overall survival, 89% of patients randomized to the chemotherapy arm subsequently received XALKORI.

Study 2 demonstrated a statistically significant improvement in PFS in the patients treated with XALKORI. Table 16 and Figure 2 summarize the efficacy results.

Table 16. Previously Treated ALK-Positive Metastatic NSCLC — Efficacy Results in Study 2
XALKORI (N=173) Chemotherapy (N=174)
HR=hazard ratio; CI=confidence interval; IRR=independent radiology review; CR=complete response; PR=partial response.
*
For pemetrexed, the median PFS was 4.2 months. For docetaxel, the median PFS was 2.6 months.
Based on the Cox proportional hazards stratified analysis.
Based on the stratified log-rank test.
§
Based on the stratified Cochran-Mantel-Haenszel test.

Progression-Free Survival (Based on IRR)

Number of Events (%)

100 (58%)

127 (73%)

Progressive Disease

84 (49%)

119 (68%)

Death

16 (9%)

8 (5%)

Median, Months (95% CI)

7.7 (6.0, 8.8)

3.0* (2.6, 4.3)

HR (95% CI)

0.49 (0.37, 0.64)

p-value

<0.001

Overall Survival

Number of Events (%)

116 (67%)

126 (72%)

Median, Months (95% CI)

21.7 (18.9,30.5)

21.9 (16.8,26.0)

HR (95% CI)

0.85 (0.66, 1.10)

p-value

0.229

Tumor Responses (Based on IRR)

Objective Response Rate % (95% CI)

65% (58, 72)

20% (14, 26)

CR, n (%)

1 (0.6%)

0

PR, n (%)

112 (65%)

34 (20%)

p-value §

<0.001

Duration of Response

Median, Months (95% CI)

7.4 (6.1, 9.7)

5.6 (3.4, 8.3)

Figure 2. Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR in Study 2
Figure 2
(click image for full-size original)

ROS1-Positive Metastatic NSCLC — Study 3 (PROFILE 1001; NCT00585195)

The efficacy and safety of XALKORI was investigated in a multicenter, single-arm study (Study 3), in which patients with ROS1-positive metastatic NSCLC received XALKORI 250 mg orally twice daily. Patients were required to have histologically-confirmed advanced NSCLC with a ROS1 rearrangement, age 18 years or older, ECOG performance status of 0, 1, or 2, and measurable disease. The efficacy outcome measures were ORR and DOR according to RECIST version 1.0 as assessed by IRR and investigator, with imaging performed every 8 weeks for the first 60 weeks.

Baseline demographic and disease characteristics were female (56%), median age of 53 years, baseline ECOG performance status of 0 or 1 (98%), White (54%), Asian (42%), past smokers (22%), never smokers (78%), metastatic disease (92%), adenocarcinoma (96%), no prior systemic therapy for metastatic disease (14%), and prior platinum-based chemotherapy for metastatic disease (80%). The ROS1 status of NSCLC tissue samples was determined by laboratory-developed break-apart FISH (96%) or RT-PCR (4%) clinical trial assays. For assessment by FISH, ROS1 positivity required that ≥15% of a minimum of 50 evaluated nuclei contained a ROS1 gene rearrangement.

Efficacy results are summarized in Table 17.

Table 17. ROS1-Positive Metastatic NSCLC — Results * in Study 3
Efficacy Parameters IRR (N=50) Investigator-Assessed (N=50)
IRR=independent radiology review; CI=confidence interval; NR=not reached.
*
As assessed by RECIST version 1.0.

Objective Response Rate (95% CI)

66% (51, 79)

72% (58, 84)

Complete Response, n

1

5

Partial Response, n

32

31

Duration of Response

Median, Months (95% CI)

18.3 (12.7, NR)

NR (14.5, NR)

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