The recent US Food and Drug Administration (FDA) approval of more than 20 new cancer drugs provides a sense of the direction in which oncology research and development is heading, according to Jiale Dai, PhD, RPh, Director, Research Pharmacy, Dana-Farber Cancer Institute, Boston. At the 2020 Hematology/Oncology Pharmacy Association (HOPA) annual conference, Dr Dai provided a brief overview of recent oncology drug approvals, with a focus on the progress made in targeting RAS, a notoriously hard-to-target mutation that he said may not be “undruggable” after all.
Many of the recently approved drugs, according to Dr Dai, are “new-and-improved” additions to drug classes that have already received FDA approval (ie, new androgen receptor inhibitors for prostate cancer or ALK inhibitors for non–small-cell lung cancer [NSCLC]). He noted several newly approved “niche” drugs, most recently tazemetostat, an EZH2 inhibitor approved for the treatment of epithelioid sarcoma, and ivosidenib, for the treatment of acute myeloid leukemia with IDH1 mutation.
Monoclonal antibodies, such as moxetumomab pasudotox and trastuzumab deruxtecan, have also been approved this year. Trastuzumab deruxtecan is very effective in patients with previously treated HER2-positive breast cancer and “has efficacy in HER2-moderate or -low breast cancer,” he said. “This is certainly an improvement over original trastuzumab.”
Overall, few first-in-class drugs are being approved by the FDA at this time, Dr Dai said. “The low-hanging fruit has been taken, so we’re getting down to more niche products, or we’re improving on antibody-drug conjugates,” he observed. “There are some very critical targets that we didn’t have the tools to target in the past, but I think researchers are developing good ways to try to tackle those.”
According to Dr Dai, the oncology drug pipeline is still very strong, with an estimated 3000 to 6000 investigational agents currently in some stage of preclinical or clinical development. In addition, the proportion of oncology drugs in the entire drug pipeline continues to rise.
Targeting the RAS Oncogene: AMG 510
Advances in oncology drugs are currently largely focused on small molecules, monoclonal antibodies, vaccines, chimeric antigen receptor T-cell therapy, oncolytic viruses, and CRISPR technology. Dr Dai homed in on recent developments with small-molecule inhibitors.
RAS is the most common oncogene with mutations, including 3 isoforms—KRAS, NRAS, and HRAS (eg, 98% of pancreatic cancers have a KRAS mutation).
The mutation profiles vary greatly between cancer types, from KRAS in pancreatic or colorectal cancer, to HRAS in head and neck squamous-cell carcinoma, to NRAS in melanoma.
According to Dr Dai, RAS is an obvious oncogenic target, but one that has proved difficult to regard as a therapeutic target, because of its lack of a drug-binding pocket and picomolar binding affinity for guanosine triphosphate (GTP); the GTP bond to RAS is very tight and is difficult to target.
“We’ve known about RAS for a long time, but targeting RAS has proved to be very challenging,” he pointed out. “It’s a very small protein, and it’s also very slippery. It’s hard to hold the covalent bond on RAS, so for many years, it’s been abandoned or regarded as an undruggable target.”
Recent research has focused on directly targeting a specific oncogenic KRAS mutation—G12C. “This RAS mutation creates a small pocket, and more important, the drug flooding this pocket is able to create a covalent bond to neighboring residue,” Dr Dai said. The 4 drugs in the pipeline include AMG 510, LY3499446, MRTX 849, and JNJ-74699157.
All 4 are oral drugs targeting the KRAS G12C mutation only.
Clinical studies have focused on solid tumors that harbor this mutation, with NSCLC currently being the biggest target for this drug. Research with AMG 510 is making the biggest strides, according to promising data from a phase 1/2 clinical trial in patients with advanced solid tumors and KRAS G12C mutations.
“The drug [AMG 510] has turned out to be very tolerable, so it’s moved along to a phase 2 trial at a dose of 960 mg once daily,” reported Dr Dai. “There’s obviously a lot of potential for this drug that can open up a tremendous amount of therapeutic opportunities—targeting different types of KRAS mutations, as well as NRAS and HRAS mutants—waiting to be explored.”
In addition, drug targeting in the RAS downstream pathway (eg, RAF—dabrafenib, vemurafenib, encorafenib; and MEK—trametinib, binimetinib, cobimetinib) may be used in combination with a RAS inhibitor.
“Interestingly, if you read review papers from 3 years ago, the research was opposed to using RAF, MEK, or PI3K targets for RAS mutation tumors, so it just goes to show how quickly the field has evolved,” Dr Dai observed.
AMG 510 also enhances the efficacy of cytotoxic or targeted therapies in preclinical models. In addition, preclinical data show that AMG 510 can induce a proinflammatory tumor microenvironment that supports the increased efficacy of checkpoint inhibitors, which suggests that it may potentially be used in combination with immunotherapy.
“A lot remains to be seen with this drug, and what it is able to do, either by itself or in combination with other agents,” Dr Dai concluded.