News and Publications
EZH2 promotes brain metastasis through immunosuppressive neutrophils: The occurrence of brain metastases severely worsens disease prognosis of many cancers and is difficult to treat. Zhang et al. recently discovered that enhancer of zeste homolog 2 (EZH2) in cancer cells promotes brain metastasis via recruitment of immunosuppressive neutrophils. EZH2 was overexpressed in brain metastases in preclinical models and in patients with breast cancer, and its genetic ablation in cancer cells improved survival and reduced brain metastases in mice. These effects were dependent on Y696 phosphorylation by Src, which facilitated downstream signaling and granulocyte colony-stimulating factor (G-CSF) expression. Intraperitoneal administration of G-CSF-blocking antibodies inhibited metastases outgrowth. Furthermore, G-CSF expression resulted in the recruitment to the brain of neutrophils expressing immunosuppressive markers. Treatment with a combination between a Src inhibitor and immune checkpoint inhibitors (ICIs) prolonged survival compared to ICIs alone. This data, published in Science, indicates that targeting the EZH2 Y696 pathway can sensitize brain metastases to immunotherapy.
- Menarini Group acquires Stemline Therapeutics in a transaction worth up to $677 million, with a potential consideration of $12.50 per share. Menarini will support further development of Stemline treatments for blastic plasmacytoid dendritic cell neoplasms.
- Alexion acquires Portola Pharmaceuticals in a deal worth $1.4 billion, to help diversify its existing drug portfolio with compounds for T and B-cell lymphomas.
- Gilead Sciences and Arcus Biosciences enter into 10-year partnership to co-develop immunotherapy products currently commercialized by Arcus. As part of this partnership, Arcus will receive $175 million in upfront payment and $200 million equity investment, in addition to a potential $1.6 billion dollars in other payments.
The Committee for Medical Products for Human Use (CHMP) adopted a positive opinion for:
- Alpelisib (Piqray, Novartis) for patients with locally advanced or metastatic breast cancer with a phosphatidylinositol-3-kinase catalytic α subunit mutation.
- Entrectinib (Rozlytreck, Roche) for use in patients whose solid tumors have a neurotrophic tyrosine receptor kinase gene fusion, or patients with proto-oncogene tyrosine-protein kinase ROS 1-positive advanced non-small cell lung cancer (NSCLC).
- Trastuzumab (Zercepac, Accord), a biosimilar for Herceptin, for treatment of breast and gastric cancers.
Extensions of indications:
- Olaparib (Lynparza, AstraZeneca) as monotherapy for the maintenance treatment of adult patients with germline breast cancer susceptibility protein (BRCA)1/2-mutations who have metastatic adenocarcinoma of the pancreas and have not progressed after a minimum of 16 weeks of platinum treatment within a first-line chemotherapy regimen.
The FDA granted approval for:
- Atezolizumab plus bevacizumab (Tecentriq plus Avastin, Genentech) for patients with unresectable/metastatic hepatocellular carcinoma who did not receive systemic therapy. Approval was based on the IMBrave150 Phase III trial, which reported an overall survival (OS) at 12 months of 67.2% with the combination vs 54.6% with sorafenib.
- Ramucirumab (Cyramza, Eli Lilly) combined with erlotinib as first-line treatment of metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations. Approval was based on the RELAY Phase III trial, which reported a statistically and clinically meaningful improvement in progression-free survival (PFS) of patients receiving the combination vs placebo (19.4 vs 12.4 months).
- Nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with two cycles of platinum-doublet chemotherapy, for first-line treatment of patients with metastatic/recurrent NSCLC, with no EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Approval was based on the CHECKMATE-9LA Phase III trial, in which a statistically significant improvement in overall survival (OS) was observed for subjects receiving the combination plus two cycles of platinum-doublet chemotherapy vs four cycles of platinum-doublet chemotherapy (14.1 vs 10.7 months).
- Brigatinib (Alunbrig, ARIAD Pharmaceuticals) for adult patients with ALK-positive metastatic NSCLC as detected by the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular), approved as a companion diagnostic for brigatinib. The approval was based on results from the ALTA 1L Phase III trial, in which brigatinib demonstrated improved progression-free survival (PFS) compared with crizotinib (24 vs 11 months).
- Olaparib (Lynparza, AstraZeneca) for patients with (suspected) deleterious germline/somatic homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer (mCRPC), who progressed following prior treatment with enzalutamide/abiraterone. This is the second approval obtained by AstraZeneca for olaparib during this month (please see below), and was based on the PROfound Phase III trial, which reported a median radiological PFS of 5.8 vs 3.5 months following olaparib vs Investigator’s choice of enzalutamide/abiraterone.
- Atezolizumab (Tecentriq, Genentech) for first-line treatment of adult patients with metastatic NSCLC whose tumors have high programmed cell death 1 ligand 1 (PD-L1) expression (PD-L1 ≥ 50% of tumor cells or PD-L1 tumor-infiltrating immune cells covering ≥ 10% of the tumor area; expression levels determined by the FDA-approved companion diagnostic Ventana PD-L1 [SP142, Ventana Medical Systems]), with no EGFR/ALK genomic tumor aberrations. Approval was based on the IMpower110 Phase III trial, which reported a median OS of 20.2 vs 13.1 months following atezolizumab vs chemotherapy.
- Ripretinib (Qinlock, Deciphera Pharmaceuticals) for adult patients with advanced gastrointestinal stromal tumors who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Approval was based on the INVICTUS Phase III trial, which reported a significant improvement in the median PFS of patients receiving ripretinib vs placebo with 6.3 vs 1.0 months.
- Rucaparib (Rubraca, Clovis Oncology), for patients with deleterious BRCA mutation (germline and/or somatic)-associated mCRPC who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. Approval was based on the TRITION2 Phase II trial, whose results reported an objective response rate (ORR) of 44% in a typically unresponsive patient population.
- Nivolumab plus ipilimumab (Opdivo plus Yervoy, Bristol-Myers Squibb), as first-line treatment for patients with metastatic NSCLC whose tumors express PD-L1 (≥1%), as determined by the PD-L1 28-8 pharmDx test, with no EGFR or ALK genomic tumor aberrations. Approval was based on the CHECKMATE-227 Phase III trial, which reported a median OS of 17.1 vs 14.9 months in patients receiving the combination vs platinum-doublet chemotherapy.
- PD-L1 28-8PharmDx (Agilent Techologies) immunohistochemistry test as a companion diagnostic device for selecting patients with NSCLC for treatment with nivolumab plus ipilimumab.
- Pomalidomide (Pomalyst, Celgene Corporation) for patients with acquired immune deficiency syndrome-related Kaposi sarcoma after failure of highly active anti-retroviral therapy and for Kaposi sarcoma in patients who are human immunodeficiency virus (HIV)-negative. Approval was based on the 12-C-0047 Phase I/II trial, which reported ORRs of 67% and 80% for the HIV-positive and, respectively, HIV-negative patients.
- Olaparib (Lynparza, AstraZeneca) combined with bevacizumab for maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete/partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency-positive status. Approval was based on the PAOLA Phase III trial, which reported a median PFS of 37.2 vs 17.7 months with combined treatment versus bevacizumab alone in patients with homologous recombination deficiency (HRD)-positive advanced ovarian cancer.
- Selpercatinib (Retevmo, Lilly), the first therapy specifically for patients with advanced rearranged during transfection (RET) fusion-positive NSCLC or advanced/metastatic RET-mutant medullary thyroid cancer (MTC). Approval was based on the LIBRETTO-001 Phase I/II trial, which reported ORRs of 85% and, respectively, 88% in patients with RET fusion-positive NSCLC naïve to systemic treatment and, respectively, in patients with RET-mutant MTC naïve to cabozantinib/vandetanib.
- Capmatinib (Tabrecta, Novartis) for adult patients with metastatic NSCLC whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. Approval was based on the GEOMETRY Phase II trial, whose results reported an ORR of 68% in treatment-naïve patients and of 41% in the previously treated patient population.
- FoundationOneCDx (Foundation Medicine) as companion diagnostic to aid in identifying patients with NSCLC for whom treatment with capmatinib may be appropriate.
- Daratumumab and hyaluronidase-fihj (Darzalex Faspro, Janssen Biotech) as a new product allowing for subcutaneous dosing of daratumumab, for treatment of adult patients with newly diagnosed or relapsed/refractory multiple myeloma. Approval was based on the COLUMBA Phase III trial, whose results reported an ORR of 41.1% vs 37.1% after combined treatment vs intravenous daratumumab alone.
The FDA also granted breakthrough therapy designation to the following drugs/devices to advance their development:
- Trastuzumab deruxtecan (Enhertu, AstraZeneca and Daiichi Sankyo), for treatment of patients with human epidermal growth factor receptor (HER2)-positive unresectable/metastatic gastric or gastroesophageal junction adenocarcinoma who have received ≥2 prior regimens including trastuzumab.
The FDA issued on 11May2020 two final guidance papers to accelerate development of products for treating/preventing the coronavirus disease (COVID-19).
- The first guidance focuses on the pre-investigational new drug (IND) process to provide drug makers feedback to progress their products into clinical trials. The FDA review and response will occur in writing in a single step. Sponsors with active INDs for drugs in development or with submitted pre-IND meeting requests should submit a new meeting request cross-referencing any existing applications. Discussions about INDs for COVID-19 should be performed through pre-IND meeting requests instead of pre-emergency use authorization requests.
- The second guidance provides recommendations for Phase II and III clinical trial design intended to establish safety and efficacy for therapeutic or prophylactic drugs for COVID-19. The guidance provides recommendations for study population, trial design, efficacy endpoints, safety, and statistical considerations, as well as a list of important clinical outcome measures.