publication date: May. 1, 2020

Drugs & Targets

FDA approves GSK’s PARP inhibitor Zejula for first-line maintenance of advanced ovarian cancer

FDA has approved a supplemental New Drug Application for Zejula (niraparib) an oral, once-daily poly (ADP-ribose) polymerase (PARP) inhibitor, as a monotherapy maintenance treatment for women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy, regardless of biomarker status.

Until now, only 20% of women with ovarian cancer, those with a BRCA mutation, were eligible to be treated with a PARP inhibitor as monotherapy in the first-line maintenance setting.

GlaxoSmithKline sponsors Zejulia.

Efficacy was investigated in PRIMA (NCT02655016), a double-blind, placebo-controlled trial that randomized 733 patients to niraparib or matched placebo. Patients were in a complete or partial response to first-line platinum-based chemotherapy. 

“PRIMA was designed for patients with ovarian cancer who have a high unmet need. The positive data observed regardless of biomarker status in this study is extremely encouraging and suggests benefit beyond the BRCAm population,” Bradley Monk, PRIMA investigator, US Oncology, University of Arizona College of Medicine, Phoenix Creighton University School of Medicine at St. Joseph’s Hospital Phoenix, said in a statement. “This approval is an important step forward in the treatment of ovarian cancer. In my opinion, maintenance treatment with niraparib should be considered an option for appropriate patients who responded to first-line platinum-based chemotherapy versus active surveillance.”

The main efficacy outcome measure, progression-free survival, was first tested in the homologous recombination deficient population, then in the overall population and was determined by blinded independent central review per RECIST 1.1. Tumor samples were tested for homologous recombination deficiency status; homologous recombination deficient was defined by either presence of tumor breast cancer susceptibility gene mutation or genomic instability score ≥42. An FDA-approved companion diagnostic is not required to initiate treatment with ZEJULA for this indication.

The trial demonstrated a statistically significant improvement in PFS for patients randomized to niraparib compared with placebo in the homologous recombination deficient and overall population. Median PFS in the homologous recombination deficient population was 21.9 months (19.3, NE) for patients receiving niraparib compared with 10.4 months (8.1, 12.1) for those receiving placebo (HR 0.43; 95% CI: 0.31, 0.59; p<0.0001). Median PFS in the overall population was 13.8 months (11.5, 14.9) for patients receiving niraparib compared with 8.2 months (7.3, 8.5) for those receiving placebo (HR 0.62; 95% CI: 0.50, 0.76; p<0.0001).

“It’s so important for patients with ovarian cancer to have treatment options, and this approval is positive news for our community,” Audra Moran, president and CEO, Ovarian Cancer Research Alliance, said in a statement. “PARP inhibitors represent a major advancement in the fight against ovarian cancer, and having a new first-line maintenance option for platinum-responsive advanced ovarian cancer patients—regardless of BRCA mutation status—is especially exciting. We are determined to keep funding research and partnering with scientists who are on the frontline of finding new treatments like this one to help those impacted by this disease.”

PRIMA study results were previously presented at the 2019 European Society for Medical Oncology (ESMO) Congress and published in the New England Journal of Medicine.


FDA grants accelerated approval to new dosing regimen for Keytruda

FDA has granted an accelerated approval to a new dosing regimen of 400 mg every six weeks for Keytruda (pembrolizumab) across all currently approved adult indications, in addition to the current 200 mg every three weeks dosing regimen.

Merck sponsors Keytruda.

The approval was based on pharmacokinetic modeling and exposure-response analyses that compared the predicted exposure of pembrolizumab 400 mg every six weeks to observed exposures of pembrolizumab in patients who received pembrolizumab at 2 mg/kg every three weeks, 200 mg every three weeks, and 10 mg/kg administered every two weeks.

The pharmacokinetic modeling was supported by additional exposure-response analyses across the pembrolizumab development program and an interim analysis of pharmacokinetics and overall response rate in a cohort of patients (Cohort B) enrolled in KEYNOTE-555 (NCT03665597), the company said. Cohort B of Study KEYNOTE-555 was an international, single-arm, multi-center study that enrolled 101 patients with advanced or metastatic melanoma who had not received prior PD-1, PD-L1, or CTLA-4 inhibitors (other than CTLA-4 inhibitors in the adjuvant setting). The ORR was 39% (95% CI: 24, 55) in the first 44 patients enrolled in KEYNOTE-555.

Merck resubmitted supplemental Biologics License Applications to FDA to update the dosing frequency for Keytruda to include a 400 mg Q6W option across all approved adult indications. The results of KEYNOTE-555 supported the resubmission, the comoany said. In the EU, 400 mg Q6W dosing for Keytruda monotherapy was approved by the European Commission in March 2019.

Results from KEYNOTE-555 Cohort B were presented in an online plenary session at the American Association for Cancer Research virtual annual meeting April 28.


FDA grants Mobocertinib Breakthrough Therapy Designation in NSCLC designation

FDA has granted Breakthrough Therapy Designation to mobocertinib (TAK-788) for the treatment of patients with metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy.

Mobocertinib is sponsored by Takeda Pharmaceutical Company Ltd.

There are no approved therapies designed to treat this specific form of NSCLC. Mobocertinib is a small-molecule tyrosine kinase inhibitor designed to selectively target EGFR and human EGFR 2 exon 20 insertion mutations.

The Breakthrough Therapy Designation is based on the overall response rate and the long-term benefit seen in patients who responded in a phase I/II study evaluating the safety and efficacy of mobocertinib in patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations and have been previously treated with systemic chemotherapy.

“Although most EGFR mutations can be targeted by currently available TKIs, people with exon 20 insertion mutations often suffer and feel forgotten since available EGFR inhibitors don’t work well in their cancer,” Jill Feldman, lung cancer patient, advocate, and co-founder of the EGFR Resisters, said in a statement.

Takeda presented development of mobocertinib, including the first public disclosure of the structure, during the American Association for Cancer Research virtual annual meeting I, April 28.

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