CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two Phase II trials

Background

Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two Phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261).

Patients and methods

Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg once daily (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS).

Results

Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% (27/50; 95% confidence interval [CI] 39, 68), and 92% (46/50; 95% CI 81, 98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS DoR (22% maturity) was not reached (range: 1–15 months); at 9 months, 75% (95% CI 53, 88) of patients were estimated to remain in response. Median follow up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population.

Conclusions

Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that previously reported.

ClinicalTrials.gov number

NCT01802632; NCT02094261

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Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with doxorubicin-based adjuvant chemotherapy (SWOG S9313)

Abstract

Background

Homologous recombination deficiency (HRD) causing alterations have been reported in triple-negative breast cancer (TNBC). We hypothesized that TNBCs with HRD alterations might be more sensitive to anthracycline plus cyclophosphamide-based chemotherapy and report on HRD status and BRCA1 promoter methylation (PM) as prognostic markers in TNBC patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG9313.

Patients and Methods

425 TNBC patients were identified from S9313. HRD score, tumor BRCA1/2 sequencing and BRCA1 PM, were performed on DNA isolated from FFPE tissue. Positive HRD status was defined as either a deleterious tumor BRCA1/2 (tBRCA) mutation and/or a pre-defined HRD score ≥ 42. Markers were tested for prognostic value on DFS and OS using Cox regression models adjusted for treatment assignment and nodal status.

Results

HRD status was determined in 89% (379/425) of cases. Of these, 67% were HRD-positive (27% with tBRCA mutation, 40% tBRCA negative but HRD score ≥42). HRD-positive status was associated with a better DFS (HR = 0.72; 95% CI 0.51– 1.00; p=0.049) and non-significant trend towards better OS (HR = 0.71; 95% CI 0.48– 1.03; p=0.073). High HRD score (≥42) in tBRCA-negative patients (n=274) was also associated with better DFS (HR = 0.64; 95% CI 0.43-0.94; p=0.023) and OS (HR = 0.65; 95% CI 0.42-1.00; p=0.049). BRCA1 PM was evaluated successfully in 82% (348/425) and detected in 32% of cases. The DFS HR for BRCA1 PM was similar to that for HRD, but did not reach statistical significance (HR = 0.79; 95% CI 0.54-1.17; p=0.25).

Conclusions

HRD positivity was observed in two-thirds of TNBC patients receiving adjuvant AC and was associated with better DFS. HRD status may identify TNBC patients who receive greater benefit from AC based chemotherapy and should be evaluated further in prospective studies.

Clinical Trials Number

Int0137 (The trial pre-dates Clinicaltrial.Gov website establishment)

from Cancer via ola Kala on Inoreader http://ift.tt/2DBgLdK
via IFTTT

Safety of an anti-PD-1 immune checkpoint inhibitor in a liver transplant recipient

anti-PD-1liver transplantation

from Cancer via ola Kala on Inoreader http://ift.tt/2phVe77
via IFTTT

Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with doxorubicin-based adjuvant chemotherapy (SWOG S9313)

Abstract

Background

Homologous recombination deficiency (HRD) causing alterations have been reported in triple-negative breast cancer (TNBC). We hypothesized that TNBCs with HRD alterations might be more sensitive to anthracycline plus cyclophosphamide-based chemotherapy and report on HRD status and BRCA1 promoter methylation (PM) as prognostic markers in TNBC patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG9313.

Patients and Methods

425 TNBC patients were identified from S9313. HRD score, tumor BRCA1/2 sequencing and BRCA1 PM, were performed on DNA isolated from FFPE tissue. Positive HRD status was defined as either a deleterious tumor BRCA1/2 (tBRCA) mutation and/or a pre-defined HRD score ≥ 42. Markers were tested for prognostic value on DFS and OS using Cox regression models adjusted for treatment assignment and nodal status.

Results

HRD status was determined in 89% (379/425) of cases. Of these, 67% were HRD-positive (27% with tBRCA mutation, 40% tBRCA negative but HRD score ≥42). HRD-positive status was associated with a better DFS (HR = 0.72; 95% CI 0.51– 1.00; p=0.049) and non-significant trend towards better OS (HR = 0.71; 95% CI 0.48– 1.03; p=0.073). High HRD score (≥42) in tBRCA-negative patients (n=274) was also associated with better DFS (HR = 0.64; 95% CI 0.43-0.94; p=0.023) and OS (HR = 0.65; 95% CI 0.42-1.00; p=0.049). BRCA1 PM was evaluated successfully in 82% (348/425) and detected in 32% of cases. The DFS HR for BRCA1 PM was similar to that for HRD, but did not reach statistical significance (HR = 0.79; 95% CI 0.54-1.17; p=0.25).

Conclusions

HRD positivity was observed in two-thirds of TNBC patients receiving adjuvant AC and was associated with better DFS. HRD status may identify TNBC patients who receive greater benefit from AC based chemotherapy and should be evaluated further in prospective studies.

Clinical Trials Number

Int0137 (The trial pre-dates Clinicaltrial.Gov website establishment)

http://ift.tt/2DBgLdK

Safety of an anti-PD-1 immune checkpoint inhibitor in a liver transplant recipient

anti-PD-1liver transplantation

http://ift.tt/2phVe77

CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two Phase II trials

Background

Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two Phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261).

Patients and methods

Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg once daily (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS).

Results

Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% (27/50; 95% confidence interval [CI] 39, 68), and 92% (46/50; 95% CI 81, 98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS DoR (22% maturity) was not reached (range: 1–15 months); at 9 months, 75% (95% CI 53, 88) of patients were estimated to remain in response. Median follow up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population.

Conclusions

Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that previously reported.

ClinicalTrials.gov number

NCT01802632; NCT02094261

http://ift.tt/2phVdA5

Four-miRNA signature as a prognostic tool for lung adenocarcinoma

http://ift.tt/2zj043p