Novel Targeted Therapies Present Opportunities in Multiple Cancer Types
Investigative and newly approved drugs targeting RET activity and KRAS-related mutations are showing deep, durable responses in several types of cancers.
A presentation at the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting outlined novel oncology therapeutics, including selective rearranged during transfection (RET) inhibitors and KRASG12C-targeting treatments.
Presenter Alexander Drilon, MD, first discussed selective RET inhibitors for RET-dependent lung and thyroid cancers. Prior to 2017, Drilon said clinicians had multi-kinase inhibitors with anti-RET activity. Since then, however, investigators have found efficacy in the use of selective RET tyrosine kinase inhibitors (TKIs) and have seen the landmark FDA approval in 2020 of the first targeted therapy for molecularly defined cohorts of RET-dependent cancers.
Selpercatinib and pralsetinib are among the new options for RET fusion-positive non-small cell lung cancer (NSCLC), according to the presentation. According to clinical trial data, investigators have found an overall response rate (ORR) of 85% for treatment-naïve patients receiving selpercatinib, and an ORR of 66% for treatment-naïve patients receiving pralsetinib.
In RET fusion-positive papillary cancers, Drilon said investigators have observed responses across various cancer types among patients receiving selpercatinib, with an ORR of 79%. These subtypes include papillary thyroid cancer, poorly differentiated thyroid cancer, anaplastic thyroid cancer, and Hürthle-cell thyroid cancer.
Notably, Drilon said these drugs are active in the central nervous system and have shown reductions in intracranial target lesions, as well as confirmed complete resolution of leptomeningeal disease. They also have significant durability in NSCLC, with a median duration of response (DoR) of 20.3 months and a median progression-free survival of 18.4 months for patients receiving selpercatinib.
Drilon noted that RET TKIs are much more tolerable than their multi-kinase inhibitor counterparts. The most common treatment-related adverse events (TRAEs) with selpercatinib include dry mouth, fatigue, peripheral edema, and diarrhea, whereas the most common TRAEs for pralsetinib include anemia, constipation, neutropenia, and others.
Finally, Drilon discussed KRASG12C mutant-targeting therapies. This mutation is found in approximately 13% of NSCLC cases and 3% of colorectal and appendix cancers, he said. Mutant-selective direct inhibitors are active in KRASG12C-mutant NSCLC, with sotorasib and adagrasib specifically showing deep responses.
In clinical trials, patients with KRASG12C mutations who received sotorasib saw a median DoR of 10 months and a median time to objective response of 1.4 months. Investigators also noted a median progression-free survival (PFS) of nearly 7 months. Adagrasib saw similar results, with a median time to response of 1.5 months.
The good thing about these inhibitors, Drilon said, is that G12C does not occur in the normal body outside of cancer cells, making it an extremely targeted approach. Furthermore, these drugs are very tolerable in the clinic setting. Researchers have noted gastrointestinal TRAEs, although these are largely not difficult to tolerate, they said.
Although the direct KRASG12C inhibitors are yet to be approved by the FDA, Drilon concluded that major developments have been made in this space. Until recently, investigators believed that KRAS was undruggable, a belief in sharp contrast to the unprecedented responses and disease control reported in prospective trials. Drilon said he hopes to see approvals of these drugs for NSCLC, as well as perhaps increased activity in other KRASG12C mutant cancers.
Drilon A. FDA Approvals and Their Incorporation Into Clinical Practice. Presented at: ASCO 2021 Annual Conference. June 4, 2021. Accessed June 7, 2021.