FDA Approval Summary: Pembrolizumab plus Lenvatinib for Endometrial Carcinoma, a Collaborative International Review under Project Orbis.

On September 17, 2019, FDA granted accelerated approval to pembrolizumab plus lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation. The submission and review of this application was conducted through an FDA Oncology Center of Excellence initiative named Project Orbis whereby the FDA, the Australian Therapeutic Goods Administration, and Health Canada were able to simultaneously review and collaborate, rendering simultaneous approval decisions in all countries. Accelerated approval of the pembrolizumab plus lenvatinib combination was based on a single-arm trial of 94 patients, with previously treated metastatic endometrial cancer whose tumors were not MSI-H/dMMR.

BH3-only BIK regulates BAX,BAK-dependent release of Ca2+ from endoplasmic reticulum stores and mitochondrial apoptosis during stress-induced cell death.

BIK, a pro-apoptotic BH3-only member of the BCL-2 family, targets the membrane of the endoplasmic reticulum (ER). It is induced in human cells in response to several stress stimuli, including genotoxic stress (radiation, doxorubicin) and overexpression of E1A or p53 but not by ER stress pathways resulting from protein malfolding. BIK initiates an early release of Ca2+ from ER upstream of the activation of effector caspases.

Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis.

The endoplasmic reticulum (ER) can elicit proapoptotic signalling that results in transmission of Ca(2+) to the mitochondria, which in turn stimulates recruitment of the fission enzyme DRP1 to the surface of the organelle. Here, we show that BH3-only BIK activates this pathway at the ER in intact cells, resulting in mitochondrial fragmentation but little release of cytochrome c to the cytosol. The BIK-induced transformations in mitochondria are dynamic in nature and involve DRP1-dependent remodelling and opening of cristae, where the major stores of cytochrome c reside.

Regulation of apoptosis by endoplasmic reticulum pathways.

Apoptotic programmed cell death pathways are activated by a diverse array of cell extrinsic and intrinsic signals, most of which are ultimately coupled to the activation of effector caspases. In many instances, this involves an obligate propagation through mitochondria, causing egress of critical proapoptotic regulators to the cytosol. Central to the regulation of the mitochondrial checkpoint is a complex three-way interplay between members of the BCL-2 family, which are comprised of an antiapoptotic subgroup including BCL-2 itself, and the proapoptotic BAX,BAK and BH3-domain-only subgroups.

Induction and endoplasmic reticulum location of BIK/NBK in response to apoptotic signaling by E1A and p53.

A DNA microarray analysis identified the BH3-only BCL-2 family member, BIK/NBK, as a transcript that is upregulated during induction of apoptosis by oncogenic E1A. E1A depended on wild-type p53 to induce BIK and activate the death program. Further, p53 independently induced BIK RNA and protein, and BIK alone stimulated cell death in p53-null cells, dependent on the activation of caspases.

BH-3-only BIK functions at the endoplasmic reticulum to stimulate cytochrome c release from mitochondria.

Stimulation of apoptosis by p53 is accompanied by induction of the BH-3-only proapoptotic member of the BCL-2 family, BIK, and ectopic expression of BIK in p53-null cells caused the release of cytochrome c from mitochondria and activation of caspases, dependent on a functional BH-3 domain. A significant fraction of BIK, which contains a predicted transmembrane segment at its COOH terminus, was found inserted in the endoplasmic reticulum (ER) membrane, with the bulk of the protein facing the cytosol. Restriction of BIK to this membrane by replacing its transmembrane segment with the ER-selective membrane anchor of cytochrome b(5) also retained the cytochrome c release and cell death-inducing activity of BIK.