publication date: Jun. 22, 2018

Drugs & Targets

FDA to review BRACAnalysis CDx sPMA as companion diagnostic for Talazoparib

Myriad Genetics Inc. said FDA has accepted its supplementary premarket approval application for BRACAnalysis CDx to be used as a companion diagnostic with Pfizer’s PARP inhibitor, talazoparib. The New Drug Application for talazoparib has been granted priority review by the FDA and has a Prescription Drug User Fee Act goal date of December 2018.

Myriad’s sPMA and Pfizer’s NDA submissions are based on results from the Pfizer-sponsored EMBRACA trial, which evaluated talazoparib versus chemotherapy in patients with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer. The primary results of the study were presented at the San Antonio Breast Cancer Symposium in Dec 2017.

Myriad estimates there are approximately 125,000 patients with metastatic breast cancer who would immediately qualify for the BRACAnalysis CDx test, followed by 60,000 new patients per year on an ongoing basis.

BRACAnalysis CDx is an in vitro diagnostic device intended for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA.  

Single nucleotide variants and small insertions and deletions are identified by polymerase chain reaction and Sanger sequencing. Large deletions and duplications in BRCA1 and BRCA2 are detected using multiplex PCR. Results of the test are used as an aid in identifying cancer patients with deleterious or suspected deleterious germline BRCA variants who may be candidates for a PARP inhibitor. This assay is for professional use only and is to be performed only at Myriad Genetic Laboratories, a single laboratory site located in Salt Lake City.


China’s drug agency approves Opdivo for previously treated NSCLC

Bristol-Myers Squibb Co, said the China National Drug Administration has approved Opdivo (nivolumab injection) for the treatment of locally advanced or metastatic non-small cell lung cancer after prior platinum-based chemotherapy in adult patients without EGFR or ALK genomic tumor aberrations.

This is China’s first and only PD-1 inhibitor and is the only immuno-oncology agent to demonstrate a survival benefit compared with chemotherapy, based on data from the pivotal phase III CheckMate -078 trial, in which 90 percent of the patients enrolled were Chinese.

The approval is based on results from the phase III CheckMate -078 trial of Opdivo vs. chemotherapy among patients with previously treated NSCLC, findings from which were presented at the American Association for Cancer Research Annual Meeting in April 2018.

In November 2017, the trial was stopped early because the independent Data Monitoring Committee concluded that Opdivo demonstrated superior overall survival compared with chemotherapy. The application later received priority review by the Center for Drug Evaluation in China.

In CheckMate -078, Opdivo reduced the risk of death by 32 percent versus chemotherapy, the primary endpoint (HR 0.68; 97.7% CI: 0.52 to 0.90; p=0.0006), in patients with previously treated NSCLC. Both efficacy and safety of Opdivo in this patient population were consistent with the results of the landmark global CheckMate -017 and -057 studies. In CheckMate -078, Grade III/IV treatment-related adverse events occurred less frequently with Opdivo versus docetaxel (10 percent vs. 48 percent). Discontinuations due to Grade III/IV TRAEs were also less frequent with Opdivo (3 percent) than with docetaxel (5 percent).

CheckMate -078 is a phase III, multinational, randomized study comparing Opdivo with docetaxel in the treatment of patients with Stage IIIb/IV NSCLC whose disease has progressed after platinum-based doublet chemotherapy.

The study was conducted primarily in China, with additional study sites in Hong Kong, Russia and Singapore. The trial randomized 504 patients (451 from China, 45 from Russia, 8 from Singapore) without EGFR mutations and with both squamous and non-squamous NSCLC, across PD-L1 expression status of <1% and ≥1%, to receive either Opdivo 3 mg/kg intravenously every two weeks (N=338) or docetaxel 75 mg/m2 intravenously every three weeks (N=166) until documented disease progression or unacceptable toxicity.

The primary endpoint was overall survival, including OS consistency observed with the global CheckMate -017 and CheckMate -057 studies. Secondary endpoints included objective response rate, progression-free survival, time to treatment failure, efficacy across subgroups, rates of treatment-related adverse events, and rate of disease-related symptom deterioration, as measured by the Lung Cancer Symptom Scale.

Minimum follow-up was 8.8 months. Median OS was 12.0 months in the Opdivo arm and 9.6 months in the chemotherapy arm (HR 0.68; 95% CI: 0.52 to 0.90; p=0.0006). Improved OS with Opdivo versus docetaxel was observed in patients with squamous (HR 0.61; 95% CI: 0.42 to 0.89) and non-squamous (HR 0.76; 95% CI: 0.56 to 1.04) tumor histology, and across all pre-defined subgroups based on tumor PD-L1 expression level.

The hazard ratios in patients with tumor PD-L1 expression ≥1% and <1% were 0.62 (95% CI: 0.45 to 0.87) and 0.75 (95% CI: 0.52 to 1.09), respectively. The ORR was 17 percent with Opdivo versus 4 percent with docetaxel. Median duration of response was not reached in the Opdivo arm versus 5.3 months in the docetaxel arm. Opdivo decreased risk of disease progression by 23 percent versus docetaxel (HR 0.77; 95% CI: 0.62 to 0.95; p=0.0147).


Natera, Institut Jules Bordet to collaborate on neoadjuvant breast cancer assay

Natera Inc. announced a research collaboration with the Institut Jules Bordet, a multidisciplinary cancer reference center in Belgium, using the company’s Signatera research-use-only circulating tumor DNA assay to evaluate molecular response and minimal residual disease in women with early stage breast cancer.

Natera will analyze approximately 300 plasma specimens prospectively collected and banked from 80 patients diagnosed with non-metastatic breast cancer, who all received neoadjuvant chemotherapy followed by surgery, and who were then monitored for recurrence with serial imaging.

The study will correlate results of the Signatera assay with clinical outcomes, including pathological response and event-free survival. With sample collection initiated in 2011, the study is led by Michail Ignatiadis, attending physician in the Medical Oncology Department of Institut Jules Bordet and assistant professor at the Université Libre de Bruxelles.

This is the third breast cancer collaboration Natera has announced in the past 18 months. Breast cancer is the second leading cause of cancer death in women in the United States. While the overall survival rate for breast cancer has improved, recurrence remains an important clinical concern, with 5-year recurrence rates estimated to be as high as 33 percent.

Signatera is the first ctDNA assay custom-built for treatment monitoring and MRD assessment. The Signatera methodology differs from currently available liquid biopsy assays, which test for a panel of genes independent of an individual’s tumor.

Signatera provides each patient with a customized blood test tailored to match the mutations found in that individual’s tumor tissue, which maximizes sensitivity and specificity. Signatera also allows researchers to track additional mutations of interest, up to several hundred mutations, for clinical studies.

In a recent study, the Signatera customized ctDNA assay demonstrated the method’s ability to detect residual disease, measure treatment response, and identify recurrence up to 11 months earlier than the standard of care for early stage non-small cell lung cancer.

Additional research presented at the 2018 American Association for Cancer Research meeting showed successful results from bladder and colorectal cancer studies, including median detection points of ctDNA that were 4.3 and 7.9 months ahead of clinical relapse detection, respectively.

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