Roche Secures Chinese Clinical Approvals for Three Investigational Oncology Drugs with Broad-Spectrum Anti-Cancer Potential

According to the latest public announcement by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration, three new drug applications for clinical trials submitted by Roche have received implicit approval. These include ipatasertib, an anticancer agent targeting the PI3K/AKT signaling pathway; the PD-L1 inhibitor atezolizumab (Tecentriq); and entrectinib, a “tumor-agnostic” personalized medicine. Notably, all three novel drugs demonstrate potential as “broad-spectrum anticancer” therapies, meaning they target specific genetic drivers of cancer rather than the tissue type of tumor origin.

Currently, no tumor-agnostic therapies have been approved in China. However, an increasing number of such therapies are entering or are in the process of entering clinical development. This suggests that Chinese patients may soon gain access to broad-spectrum anticancer treatments, ushering in a new era of tumor-agnostic oncology.

Ipatasertib: Targeting the PI3K/AKT Signaling Pathway

Ipatasertib is an oral, selective inhibitor targeting the PI3K/AKT signaling pathway, capable of binding to all three AKT isoforms. The PI3K/AKT signaling pathway is one of the most highly active pathways that promote tumorigenesis, drug resistance, and metabolic alterations, and is considered a mechanism by which tumor cells develop resistance to immune checkpoint inhibitors. Therefore, inhibition of the PI3K/AKT signaling pathway can prevent cancer cell growth and survival, and may also reverse tumor cell resistance to immunotherapy.

Ipatasertib has been approved for clinical trials in China, with plans to develop it for the treatment of AKT1/2/3 mutation-positive solid tumors. Studies have shown that dysregulation of the PI3K/AKT signaling pathway is present in nearly all human cancers, including breast cancer, colorectal cancer, and hematologic malignancies. Therefore, AKT is considered a novel broad-spectrum anticancer target.

Source: CDE Official Website

Previously, ipatasertib met one of the primary endpoints in a Phase 3 clinical trial involving patients with metastatic castration-resistant prostate cancer (mCRPC). In patients harboring deletions of the PTEN tumor suppressor gene, ipatasertib-based combination therapy significantly improved radiographic progression-free survival (rPFS).

In the treatment of triple-negative breast cancer (TNBC), results from a Phase 1b clinical trial evaluating ipatasertib in combination with atezolizumab and chemotherapy as first-line therapy for TNBC demonstrated an objective response rate (ORR) of 73%, irrespective of patients’ PD-L1 expression status or PIK3CA/AKT1/PTEN genetic alterations. Another Phase 2 clinical trial, named LOTUS, showed that ipatasertib reduced the risk of disease progression and death by 56% in patients with TNBC selected through molecular diagnostic screening.

Atezolizumab: PD-L1 Inhibitor

Atezolizumab is an anti-PD-L1 monoclonal antibody developed by Genentech, a member of the Roche Group. It identifies and attacks tumor cells by binding to PD-L1 proteins on the surface of tumor cells and tumor-infiltrating immune cells. Previously, this product has been approved globally for multiple indications, including bladder cancer, urothelial carcinoma, non-small cell lung cancer, and extensive-stage small cell lung cancer. Notably, multiple clinical trials are currently evaluating the efficacy of PD-L1 inhibitors in "tumor-agnostic" indications.

Atezolizumab has been approved for clinical development in China, with two intended indications. The first is the combination of atezolizumab, albumin-bound paclitaxel, and metformin for patients with previously untreated metastatic triple-negative breast cancer. The second is the combination of atezolizumab plus bevacizumab with cisplatin and gemcitabine for patients with advanced biliary tract cancer who have not previously received systemic therapy.

Source: CDE Official Website

In the treatment of triple-negative breast cancer (TNBC), atezolizumab was approved in the United States in March 2019, in combination with nab-paclitaxel, for adult patients with unresectable locally advanced or metastatic TNBC. In the Phase 3 clinical trial named IMpassion130, this combination therapy reduced the risk of disease progression and death by 40%, achieving a median progression-free survival (PFS) of 7.4 months (vs. 4.8 months). Early studies on metformin for TNBC have been published in journals such as Nature, demonstrating that in animal tumor models, metformin combined with heme, PD-1 antibodies, BCL-2 inhibitors, and other agents exerted cytotoxic effects against breast tumor cells. These findings provide a scientific rationale for the combination of atezolizumab and metformin in the treatment of TNBC.

In the treatment of advanced biliary tract cancer, results from a randomized, multicenter Phase 2 study presented at the 2020 American Association for Cancer Research (AACR) Annual Meeting demonstrated that atezolizumab in combination with the MEK inhibitor cobimetinib met its primary endpoint and significantly prolonged progression-free survival compared to atezolizumab monotherapy.

Notably, atezolizumab was approved in China in February this year for first-line treatment of extensive-stage small cell lung cancer, and its new indication for first-line treatment of advanced unresectable hepatocellular carcinoma was re-approved in October this year.

Entrectinib: Targeting ROS1 and NTRK Gene Fusions

Entrectinib is a selective tyrosine kinase inhibitor designed to target NTRK and ROS1 gene fusions, capable of inhibiting the kinase activity of TRK A/B/C and ROS1. NTRK gene fusions may occur in tumors originating from various anatomical sites, including breast cancer, cholangiocarcinoma, colorectal cancer, neuroendocrine tumors, non-small cell lung cancer (NSCLC), and pancreatic cancer. Studies have demonstrated that this “tumor-agnostic” precision anticancer therapy achieved an objective response rate of 57.4% in patients with NTRK fusion-positive solid tumors, along with an intracranial objective response rate of 54.5%.

Entrectinib capsules/tablets have received three implied approvals for clinical trials from the Center for Drug Evaluation (CDE), with all proposed indications being: for the treatment of patients with unresectable, locally advanced or metastatic solid tumors harboring specific oncogenic alterations or potential predictive biomarkers. Previously, this product had also been approved for multiple clinical trials in China, with indications including: pediatric patients with NTRK-positive solid tumors, patients with ROS1-positive locally advanced or metastatic non-small cell lung cancer, and patients with locally advanced or metastatic solid tumors harboring NTRK1/2/3 gene mutations.

Source: CDE Official Website

Notably, the tumor-agnostic indication for entrectinib received accelerated approval from the U.S. FDA in August 2019 for the treatment of adult and adolescent cancer patients harboring NTRK gene fusions, becoming the third tumor-agnostic anticancer therapy approved by the U.S. FDA. Meanwhile, the product was also approved for patients with non-small cell lung cancer (NSCLC) carrying ROS1 gene mutations.

References:

[1] Center for Drug Evaluation, National Medical Products Administration of China. Retrieved Nov 26, 2020, from http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=21#

[2] Roche’s IPATential150 study evaluating ipatasertib in combination with abiraterone and prednisone/prednisolone met one of its co-primary endpoints. Retrieved June 20, 2020, from https://www.roche.com/media/releases/med-cor-2020-06-19.htm

[3] Roche's ipatasertib in combination with Tecentriq and chemotherapy shows promising anti-tumour activity in triple-negative breast cancer in early phase trial. Retrieved April 1, 2019, from https://www.globenewswire.com/news-release/2019/04/01/1790294/0/en/Roche-s-ipatasertib-in-combination-with-Tecentriq-and-chemotherapy-shows-promising-anti-tumour-activity-in-triple-negative-breast-cancer-in-early-phase-trial.html

[4]Japan becomes the first country to approve Roche’s personalised medicine Rozlytrek. Retrieved June 18, 2019, from https://www.roche.com/media/releases/med-cor-2019-06-18.htm

[5] FDA approves third oncology drug that targets a key genetic driver of cancer, rather than a specific type of tumor. Retrieved August 15, 2019, from https://www.prnewswire.com/news-releases/fda-approves-third-oncology-drug-that-targets-a-key-genetic-driver-of-cancer-rather-than-a-specific-type-of-tumor-300902681.html

[6] Roche’s Tecentriq-based immunotherapy combination regimen approved in China for the treatment of hepatocellular carcinoma. Retrieved Oct 28, 2020, from Roche’s official WeChat account

Source: Yiyao Guanlan

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