New targeted therapies present opportunities in several types of cancer
A presentation at the 2021 American Society of Clinical Oncology (ASCO) annual meeting described new oncology therapies, including selective inhibitors rearranged during transfection (RET) and KRASTreatments targeting G12C.
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, researchers have found efficacy in the use of selective tyrosine kinase (TKI) inhibitors and have seen the historic FDA approval in 2020 of the first targeted therapy for molecularly defined cohorts of cancers. RET-dependent.
According to the presentation, selpercatinib and pralsetinib are among the new options for non-small cell lung cancer (NSCLC) with RET fusion. Based on clinical trial data, investigators 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 papillary cancers positive for the RET fusion, Drilon said researchers observed responses on various types of cancer in patients receiving selpercatinib, with an RRT of 79%. These subtypes include papillary thyroid cancer, poorly differentiated thyroid cancer, anaplastic thyroid cancer, and Hürthle cell thyroid cancer.
Notably, Drilon said that these drugs are active in the central nervous system and have shown a reduction in target intracranial lesions, as well as a 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 (RTEs) with selpercatinib include dry mouth, fatigue, peripheral edema, and diarrhea, while the most common RARs for pralsetinib include anemia, constipation, neutropenia and others.
Finally, Drilon discussed KRASTherapies targeting G12C mutants. This mutation is found in about 13% of NSCLC cases and 3% of colorectal and appendix cancers, he said. Direct selective mutant inhibitors are active in KRASNSCLC G12C-mutant, with sotorasib and adagrasib specifically showing deep responses.
In clinical trials, patients with KRASG12C mutations that 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 obtained similar results, with a median time to response of 1.5 months.
The good thing about these inhibitors, Drilon said, is that G12C doesn’t occur in the normal body outside of cancer cells, making it an extremely targeted approach. In addition, these drugs are very tolerable in clinical settings. The researchers noted gastrointestinal TRAE, although these were generally not difficult to tolerate, they said.
Although the direct KRASG12C inhibitors have not yet been approved by the FDA, Drilon concluded that major developments have been made in this area. Until recently, investigators believed that KRAS was undrugable, a belief in stark contrast to the unprecedented responses and disease control reported in prospective trials. Drilon said he hoped to see the approval of these drugs for the NSCLC, as well as possibly increased activity in others. KRASG12C mutant cancers.
Drilon A. FDA approvals and their incorporation into clinical practice. Presented at the ASCO 2021 Annual Conference. June 4, 2021. Accessed June 7, 2021.