Drug Active in ‘Undruggable’ KRAS-Mutant NSCLC
A small-molecule inhibitor targeting a KRAS mutation achieved a high rate of disease control in a preliminary study of patients with non-small cell lung cancer (NSCLC).
A third of patients with NSCLC had objective responses with sotorasib, and 88.1% attained disease control. The disease control rate (DCR) surpassed 90% in the subgroup of patients who received the recommended phase II dose of the drug.
No dose-limiting toxicity was observed, and grade 3/4 treatment-related adverse events (TRAEs) were manageable in most cases, reported David Hong, MD, of the University of Texas MD Anderson Cancer Center in Houston, during the 2020 European Society for Medical Oncology (ESMO) virtual meeting.
“Sotorasib has shown a favorable safety profile and demonstrated durable disease control in heavily pretreated patients with non-small cell lung cancer,” said Hong. “Sotorasib demonstrated clinical activity across a range of different biomarkers. A range of clinical trials evaluating sotorasib as monotherapy or in combination with other anticancer agents are currently underway.”
The results were reported simultaneously in the New England Journal of Medicine (NEJM), including data from a subgroup of patients with colorectal cancer (CRC).
Despite being the most commonly mutated oncogene in human cancers, KRAS has no FDA-approved therapies that target it. KRAS mutations often are associated with therapeutic resistance and poor outcomes. The KRAS p.G12C mutation occurs in approximately 13% of NSCLCs, 3%-5% of CRCs, and 1%-3% other solid tumors, Hong noted.
Sotorasib specifically and irreversibly inhibits KRASG12C and traps the protein in its inactive state. In preclinical studies, sotorasib produced durable complete tumor regression, providing the basis for a phase I trial to evaluate the drug’s safety, pharmacokinetics, and efficacy in patients with advanced solid tumors harboring the KRAS p.G12C mutation.
Investigators in the multicenter trial recruited adults with histologically confirmed, locally advanced or metastatic cancers associated with the KRAS p.G12C mutation. Patients with untreated brain metastases or recent systemic or radiation therapy were excluded.
Patients received oral sotorasib daily until disease progression or development of unacceptable toxicity. The dose-escalation trial evaluated sotorasib at doses of 180 to 960 mg/day, the latter being chosen as the recommended phase II dose. The primary endpoint was safety, and secondary endpoints included various pharmacokinetic parameters, objective response, duration of response, disease control, progression-free survival (PFS), and duration of stable disease.
Data analysis included 129 patients, but Hong limited his ESMO discussion to the subgroup of 59 patients with advanced/metastatic NSCLC.
No dose-limiting toxicities were reported during the trial. TRAEs occurred in 39 (66.1%) of the NSCLC subgroup, including grade 3/4 events in 12 (20.5%) patients. One patient discontinued treatment because of an AE.
The NSCLC subgroup had a median follow-up of 11.7 months, and 19 participants had a partial response. An additional 33 patients had stable disease for at least 6 weeks. Median duration of response was 10.9 months, and responses were observed at all dose levels evaluated in the trial. Among the 34 patients who received the recommended phase II dose, 12 (35.3%) had partial responses, and 19 (55.9%) had stable disease, resulting in a DCR of 91.2%.
Hong reported that 42 of the 59 patients had some degree of tumor shrinkage. The subgroup had a median PFS of 6.3 months.
As reported in NEJM, the study population included 42 patients with CRC, who had a median follow-up of 12.8 months. Three patients had confirmed partial responses persisting for 4.9 to 9.9 months. An additional 28 patients had stable disease, resulting in a DCR of 73.8%. The subgroup had a median PFS of 4.0 months.
Of the 28 patients with other types of tumors, four partial responses were confirmed (pancreatic, endometrial, and appendiceal cancers and melanoma) and 17 patients had stable disease. Response duration ranged from 4.4 to 6.9 months.
Patients with advanced KRASG12CNSCLC or CRC have an overall survival of 1 to 2 years, a statistic that has fueled a nearly 4 decade-long search for an effective KRAS-targeted drug, noted authors of an accompanying NEJM editorial.
The findings from the phase I study are “very encouraging, showing the first step in ‘drugging the undruggable,’ wrote Patricia M. LoRusso, DO, of the Yale Cancer Center in New Haven, Connecticut, and Judith S. Sebolt-Leopold, PhD, of the University of Michigan in Ann Arbor.
“The article by Hong et al shows that, through meaningful scientific collaborations, clinical inhibition of this previously untouchable target is now possible,” LoRusso and Sebolt-Leopold added. “The early development of KRASG12C-targeted agents is just the beginning, lending hope that the ability to target not only other KRAS mutations but also other targets previously thought to be undruggable may be within reach.”
Last Updated September 20, 2020
The study was supported by Amgen.
Hong disclosed relevant relationships with AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, Medimmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics, Alpha Insights, Acuta, Axiom, Baxter, COG, Ecort, GLG, Group H, Guidepoint, Janssen, Merrimack, Medscape, Numab, Prime Oncology, Trieza Therapeutics, WebMD, molecular Match, OncoResponse, and Presagia.