LORBRENA® Clinical Studies

(lorlatinib)

14 CLINICAL STUDIES

Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study)

The efficacy of LORBRENA for the treatment of patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease was established in an open-label, randomized, active-controlled, multicenter study (Study B7461006; NCT03052608). Patients were required to have an ECOG performance status of 0–2 and ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay. Neurologically stable patients with treated or untreated asymptomatic CNS metastases, including leptomeningeal metastases, were eligible. Patients were required to have finished radiation therapy, at least 2 weeks (for stereotactic or partial radiation) or 4 weeks (for whole brain irradiation) prior to randomization. Patients with severe acute or chronic psychiatric conditions, including recent (within the past year) or active suicidal ideation or behavior, were excluded.

Patients were randomized 1:1 to receive LORBRENA 100 mg orally once daily or crizotinib 250 mg orally twice daily. Randomization was stratified by ethnic origin (Asian vs. non-Asian) and the presence or absence of CNS metastases at baseline. Treatment on both arms was continued until disease progression or unacceptable toxicity. The major efficacy outcome measure was progression-free survival (PFS) as determined by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). Additional efficacy outcome measures were overall survival (OS) and tumor assessment related data by BICR, including overall response rate (ORR), and duration of response (DOR). In patients with measurable CNS metastases at baseline, additional outcome measures were intracranial overall response rate (IC-ORR) and intracranial duration of response (IC-DOR) by BICR.

A total of 296 patients were randomized to LORBRENA (n=149) or crizotinib (n=147). The demographic characteristics of the overall study population were: median age 59 years (range: 26 to 90 years), age ≥65 years (35%), 59% female, 49% White, 44% Asian, and 0.3% Black. The ECOG performance status at baseline was 0 or 1 in 96% of patients. The majority of patients had adenocarcinoma (95%) and never smoked (59%). CNS metastases were present in 26% (n=78) of patients: of these, 30 patients had measurable CNS lesions.

Efficacy results from Study B7461006 as assessed by BICR are summarized in Table 6 and Figure 1. Results demonstrated a significant improvement in PFS for the LORBRENA arm over the crizotinib arm. At the data cutoff point OS data was not mature.

Table 6 Efficacy Results in Study B7461006 (CROWN)
Efficacy ParameterLORBRENA
N=149
Crizotinib
N=147
Abbreviations: CI=confidence interval; N=number of patients; NE=not estimable; PFS=progression free survival.
*
Based on the Brookmeyer and Crowley method.
Hazard ratio based on Cox proportional hazards model.
p-value based on 1-sided stratified log-rank test.
§
Using exact method based on binomial distribution.

Progression-free survival

  Number of events, n (%)

41 (28%)

86 (59%)

    Progressive disease, n (%)

32 (22%)

82 (56%)

    Death, n (%)

9 (6%)

4 (3%)

  Median, months (95% CI)*

NE (NE, NE)

9.3 (7.6, 11.1)

  Hazard ratio (95% CI)

0.28 (0.19, 0.41)

  p-value

<0.0001

Overall response rate

  Overall response rate (95% CI)§

76% (68, 83)

58% (49, 66)

  Complete response

3%

0%

  Partial response

73%

58%

Duration of response

  Number of responders, n

113

85

  Median, months (Range)

NE (0.9, 31.3)

11 (1.1, 27.5)

  Response duration ≥6 months, n (%)

101 (89%)

53 (62%)

  Response duration ≥12 months, n (%)

79 (70%)

23 (27%)

  Response duration ≥18 months, n (%)

34 (30%)

9 (11%)

Figure 1: Kaplan-Meier Plot of Progression-Free Survival by BICR in Study B7461006 (CROWN)

Figure 1

The results of prespecified exploratory analyses of intracranial response rate in 30 patients with measurable CNS lesions at baseline as assessed by BICR are summarized in Table 7.

Table 7 Intracranial Response Rate in Patients with Measurable Intracranial Lesions in CROWN
Intracranial Tumor Response AssessmentLORBRENA
N=17
Crizotinib
N=13
Abbreviations: CI=confidence interval; N/n=number of patients.
*
Using exact method based on binomial distribution.

Intracranial response rate (95% CI)*

82% (57, 96)

23% (5, 54)

  Complete response

71%

8%

Duration of response

  Number of responders, n

14

3

  Response duration ≥12 months, n (%)

11 (79%)

0

ALK-Positive Metastatic NSCLC Previously Treated with an ALK Kinase Inhibitor

The efficacy of LORBRENA was demonstrated in a subgroup of patients with ALK-positive metastatic NSCLC previously treated with one or more ALK kinase inhibitors who were enrolled in a non-randomized, dose-ranging and activity-estimating, multi-cohort, multicenter study (Study B7461001; NCT01970865). Patients included in this subgroup were required to have metastatic disease with at least 1 measurable target lesion according to RECIST v1.1, ECOG performance status of 0 to 2, and documented ALK rearrangement in tumor tissue as determined by fluorescence in situ hybridization (FISH) assay or by Immunohistochemistry (IHC), and received LORBRENA 100 mg orally once daily. Patients with asymptomatic CNS metastases, including patients with stable or decreasing steroid use within 2 weeks prior to study entry, were eligible. Patients with severe, acute, or chronic psychiatric conditions including suicidal ideation or behavior were excluded. In addition, for patients with ALK-positive metastatic NSCLC, the extent and type of prior treatment was specified for each individual cohort (see Table 8). The major efficacy outcome measures were ORR and intracranial ORR, according to RECIST v1.1, as assessed by Independent Central Review (ICR) committee. Data were pooled across all subgroups listed in Table 8. Additional efficacy outcome measures included DOR, and intracranial DOR.

A total of 215 patients were enrolled across the subgroups in Table 8. The distribution of patients by type and extent of prior therapy is provided in Table 8. The demographic characteristics across all 215 patients were: 59% female, 51% White, 34% Asian, and the median age was 53 years (29 to 85 years) with 18% of patients ≥65 years. The ECOG performance status at baseline was 0 or 1 in 96% of patients. All patients had metastatic disease and 95% had adenocarcinoma. Brain metastases as identified by ICR were present in 69% of patients; of these, 60% had received prior radiation to the brain and 60% (n=89) had measurable disease per ICR.

Table 8 Extent of Prior Therapy in the Subgroup of Patients with Previously Treated ALK-Positive Metastatic NSCLC in Study B7461001
Extent of prior therapyNumber of patients
Abbreviations: ALK=anaplastic lymphoma kinase; NSCLC=non-small cell lung cancer.
*
Chemotherapy administered in the metastatic setting.

Prior crizotinib and no prior chemotherapy*

29

Prior crizotinib and 1–2 lines of prior chemotherapy*

35

Prior ALK inhibitor (not crizotinib) with or without prior chemotherapy*

28

Two prior ALK inhibitors with or without prior chemotherapy*

75

Three prior ALK inhibitors with or without prior chemotherapy*

48

Total

215

Efficacy results for Study B7461001 are summarized in Tables 9 and 10.

Table 9 Efficacy Results in Study B7461001
Efficacy ParameterOverall
N=215
Abbreviations: CI=confidence interval; N=number of patients.
*
Per Independent Central Review.
Using exact method based on binomial distribution.
Estimated using the Kaplan-Meier method.

Overall response rate* (95% CI)

48% (42, 55)

  Complete response

4%

  Partial response

44%

Duration of response

  Median, months (95% CI)

12.5 (8.4, 23.7)

An assessment of intracranial ORR and the duration of response for CNS metastases in the subgroup of 89 patients in Study B7461001 with baseline measurable lesions in the CNS according to RECIST v1.1 are summarized in Table 10. Of these, 56 (63%) patients received prior brain radiation, including 42 patients (47%) who completed brain radiation treatment at least 6 months before starting treatment with LORBRENA.

Table 10 Intracranial Response Rate in Patients with Measurable Intracranial Lesions in Study B7461001
Efficacy ParameterIntracranial
N=89
Abbreviations: CI=confidence interval; N=number of patients; NR=not reached.
*
Per Independent Central Review.
Using exact method based on binomial distribution.
Estimated using the Kaplan-Meier method.

Intracranial response rate* (95% CI)

60% (49, 70)

  Complete response

21%

  Partial response

38%

Duration of response

  Median, months (95% CI)

19.5 (12.4, NR)

In exploratory analyses conducted in subgroups defined by prior therapy, the response rates to LORBRENA were:

ORR = 39% (95% CI: 30, 48) in 119 patients who received crizotinib and at least one other ALK inhibitor, with or without prior chemotherapy
ORR = 31% (95% CI: 9, 61) in 13 patients who received alectinib as their only ALK inhibitor, with or without prior chemotherapy
ORR = 46% (95% CI: 19, 75) in 13 patients who received ceritinib as their only ALK inhibitor, with or without prior chemotherapy

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Clinical Studies

14 CLINICAL STUDIES

Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study)

The efficacy of LORBRENA for the treatment of patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease was established in an open-label, randomized, active-controlled, multicenter study (Study B7461006; NCT03052608). Patients were required to have an ECOG performance status of 0–2 and ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay. Neurologically stable patients with treated or untreated asymptomatic CNS metastases, including leptomeningeal metastases, were eligible. Patients were required to have finished radiation therapy, at least 2 weeks (for stereotactic or partial radiation) or 4 weeks (for whole brain irradiation) prior to randomization. Patients with severe acute or chronic psychiatric conditions, including recent (within the past year) or active suicidal ideation or behavior, were excluded.

Patients were randomized 1:1 to receive LORBRENA 100 mg orally once daily or crizotinib 250 mg orally twice daily. Randomization was stratified by ethnic origin (Asian vs. non-Asian) and the presence or absence of CNS metastases at baseline. Treatment on both arms was continued until disease progression or unacceptable toxicity. The major efficacy outcome measure was progression-free survival (PFS) as determined by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). Additional efficacy outcome measures were overall survival (OS) and tumor assessment related data by BICR, including overall response rate (ORR), and duration of response (DOR). In patients with measurable CNS metastases at baseline, additional outcome measures were intracranial overall response rate (IC-ORR) and intracranial duration of response (IC-DOR) by BICR.

A total of 296 patients were randomized to LORBRENA (n=149) or crizotinib (n=147). The demographic characteristics of the overall study population were: median age 59 years (range: 26 to 90 years), age ≥65 years (35%), 59% female, 49% White, 44% Asian, and 0.3% Black. The ECOG performance status at baseline was 0 or 1 in 96% of patients. The majority of patients had adenocarcinoma (95%) and never smoked (59%). CNS metastases were present in 26% (n=78) of patients: of these, 30 patients had measurable CNS lesions.

Efficacy results from Study B7461006 as assessed by BICR are summarized in Table 6 and Figure 1. Results demonstrated a significant improvement in PFS for the LORBRENA arm over the crizotinib arm. At the data cutoff point OS data was not mature.

Table 6 Efficacy Results in Study B7461006 (CROWN)
Efficacy ParameterLORBRENA
N=149
Crizotinib
N=147
Abbreviations: CI=confidence interval; N=number of patients; NE=not estimable; PFS=progression free survival.
*
Based on the Brookmeyer and Crowley method.
Hazard ratio based on Cox proportional hazards model.
p-value based on 1-sided stratified log-rank test.
§
Using exact method based on binomial distribution.

Progression-free survival

  Number of events, n (%)

41 (28%)

86 (59%)

    Progressive disease, n (%)

32 (22%)

82 (56%)

    Death, n (%)

9 (6%)

4 (3%)

  Median, months (95% CI)*

NE (NE, NE)

9.3 (7.6, 11.1)

  Hazard ratio (95% CI)

0.28 (0.19, 0.41)

  p-value

<0.0001

Overall response rate

  Overall response rate (95% CI)§

76% (68, 83)

58% (49, 66)

  Complete response

3%

0%

  Partial response

73%

58%

Duration of response

  Number of responders, n

113

85

  Median, months (Range)

NE (0.9, 31.3)

11 (1.1, 27.5)

  Response duration ≥6 months, n (%)

101 (89%)

53 (62%)

  Response duration ≥12 months, n (%)

79 (70%)

23 (27%)

  Response duration ≥18 months, n (%)

34 (30%)

9 (11%)

Figure 1: Kaplan-Meier Plot of Progression-Free Survival by BICR in Study B7461006 (CROWN)

Figure 1

The results of prespecified exploratory analyses of intracranial response rate in 30 patients with measurable CNS lesions at baseline as assessed by BICR are summarized in Table 7.

Table 7 Intracranial Response Rate in Patients with Measurable Intracranial Lesions in CROWN
Intracranial Tumor Response AssessmentLORBRENA
N=17
Crizotinib
N=13
Abbreviations: CI=confidence interval; N/n=number of patients.
*
Using exact method based on binomial distribution.

Intracranial response rate (95% CI)*

82% (57, 96)

23% (5, 54)

  Complete response

71%

8%

Duration of response

  Number of responders, n

14

3

  Response duration ≥12 months, n (%)

11 (79%)

0

ALK-Positive Metastatic NSCLC Previously Treated with an ALK Kinase Inhibitor

The efficacy of LORBRENA was demonstrated in a subgroup of patients with ALK-positive metastatic NSCLC previously treated with one or more ALK kinase inhibitors who were enrolled in a non-randomized, dose-ranging and activity-estimating, multi-cohort, multicenter study (Study B7461001; NCT01970865). Patients included in this subgroup were required to have metastatic disease with at least 1 measurable target lesion according to RECIST v1.1, ECOG performance status of 0 to 2, and documented ALK rearrangement in tumor tissue as determined by fluorescence in situ hybridization (FISH) assay or by Immunohistochemistry (IHC), and received LORBRENA 100 mg orally once daily. Patients with asymptomatic CNS metastases, including patients with stable or decreasing steroid use within 2 weeks prior to study entry, were eligible. Patients with severe, acute, or chronic psychiatric conditions including suicidal ideation or behavior were excluded. In addition, for patients with ALK-positive metastatic NSCLC, the extent and type of prior treatment was specified for each individual cohort (see Table 8). The major efficacy outcome measures were ORR and intracranial ORR, according to RECIST v1.1, as assessed by Independent Central Review (ICR) committee. Data were pooled across all subgroups listed in Table 8. Additional efficacy outcome measures included DOR, and intracranial DOR.

A total of 215 patients were enrolled across the subgroups in Table 8. The distribution of patients by type and extent of prior therapy is provided in Table 8. The demographic characteristics across all 215 patients were: 59% female, 51% White, 34% Asian, and the median age was 53 years (29 to 85 years) with 18% of patients ≥65 years. The ECOG performance status at baseline was 0 or 1 in 96% of patients. All patients had metastatic disease and 95% had adenocarcinoma. Brain metastases as identified by ICR were present in 69% of patients; of these, 60% had received prior radiation to the brain and 60% (n=89) had measurable disease per ICR.

Table 8 Extent of Prior Therapy in the Subgroup of Patients with Previously Treated ALK-Positive Metastatic NSCLC in Study B7461001
Extent of prior therapyNumber of patients
Abbreviations: ALK=anaplastic lymphoma kinase; NSCLC=non-small cell lung cancer.
*
Chemotherapy administered in the metastatic setting.

Prior crizotinib and no prior chemotherapy*

29

Prior crizotinib and 1–2 lines of prior chemotherapy*

35

Prior ALK inhibitor (not crizotinib) with or without prior chemotherapy*

28

Two prior ALK inhibitors with or without prior chemotherapy*

75

Three prior ALK inhibitors with or without prior chemotherapy*

48

Total

215

Efficacy results for Study B7461001 are summarized in Tables 9 and 10.

Table 9 Efficacy Results in Study B7461001
Efficacy ParameterOverall
N=215
Abbreviations: CI=confidence interval; N=number of patients.
*
Per Independent Central Review.
Using exact method based on binomial distribution.
Estimated using the Kaplan-Meier method.

Overall response rate* (95% CI)

48% (42, 55)

  Complete response

4%

  Partial response

44%

Duration of response

  Median, months (95% CI)

12.5 (8.4, 23.7)

An assessment of intracranial ORR and the duration of response for CNS metastases in the subgroup of 89 patients in Study B7461001 with baseline measurable lesions in the CNS according to RECIST v1.1 are summarized in Table 10. Of these, 56 (63%) patients received prior brain radiation, including 42 patients (47%) who completed brain radiation treatment at least 6 months before starting treatment with LORBRENA.

Table 10 Intracranial Response Rate in Patients with Measurable Intracranial Lesions in Study B7461001
Efficacy ParameterIntracranial
N=89
Abbreviations: CI=confidence interval; N=number of patients; NR=not reached.
*
Per Independent Central Review.
Using exact method based on binomial distribution.
Estimated using the Kaplan-Meier method.

Intracranial response rate* (95% CI)

60% (49, 70)

  Complete response

21%

  Partial response

38%

Duration of response

  Median, months (95% CI)

19.5 (12.4, NR)

In exploratory analyses conducted in subgroups defined by prior therapy, the response rates to LORBRENA were:

ORR = 39% (95% CI: 30, 48) in 119 patients who received crizotinib and at least one other ALK inhibitor, with or without prior chemotherapy
ORR = 31% (95% CI: 9, 61) in 13 patients who received alectinib as their only ALK inhibitor, with or without prior chemotherapy
ORR = 46% (95% CI: 19, 75) in 13 patients who received ceritinib as their only ALK inhibitor, with or without prior chemotherapy
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