By Janelle E. Mann, PharmD, BCOP
What is sotorasib?
Sotorasib is an oral molecule which specifically and irreversibly inhibits KRAS G12C, a mutant-oncogenic form of the RAS GTPase, KRAS. Sotorasib is a RAS inhibitor which irreversibly and covalently binds to KRAS G12C. In the inactive state of mutant KRAS G12C, the mutant cysteine resides next to a narrow surface pocket, the P2 pocket. Sotorasib binds with the unique cysteine of KRAS G12C through an interaction with the P2 pocket, locking the protein in an inactive state which prevents downstream signaling, leading to inhibition of cell growth and promoting apoptosis only in KRAS G12C tumor cell lines.
What is this approved for?
Sotorasib is approved for adults with non-small cell lung cancer (NSCLC) whose tumors have a KRAS G12C mutation and have received at least one prior systemic therapy. This is the first approved targeted therapy for KRAS-mutant cancers. Of all KRAS mutations, KRAS G12C is the most common in lung adenocarcinoma. KRAS G12C accounts for 13 percent of mutations seen in lung adenocarcinoma. Sotorasib is specific for KRAS G12C mutant lung cancer. Sotorasib received FDA approval through the accelerated approval pathway and was granted fast track, priority review, breakthrough therapy, and orphan drug designation.
What is the basis for this approval?
Sotorasib was approved for previously treated KRAS G12C-mutated NSCLC patients based on results from the CodeBreaK 100 trial (N Engl J Med 2021;384(25):2371-81). The trial was a multicenter, single-group, open-label, Phase II trial of sotorasib at 960 mg by mouth daily as monotherapy in patients with locally advanced or metastatic KRAS G12C-mutated NSCLC. A total of 124 patients had measurable disease at baseline and were evaluated for response. The primary endpoint was objective response (complete or partial response). The observed objective response was 37.1 percent [95%CI, 28.6-46.2], with 3.2 percent complete response and 33.9 percent partial response. Key secondary endpoints observed were median duration of response, which was 11.1 months, a median progression-free survival of 6.8 months, and median overall survival 12.5 months. Treatment-related adverse events occurred in 69.8 percent patients, including Grade 3 at 19.8 percent and Grade 4 at 0.8 percent.
How do you administer this drug?
Sotorasib starting dose of 960 mg and is administered as 8 x 120 mg tablets taken by mouth daily with or without food. Tablets should be swallowed whole and not crushed.
Are there any premedications needed for sotorasib?
No premedications are required for sotorasib. It is listed as minimal or low (<30%) emetic potential.
What are the common side effects associated with sotorasib (> or = 10%)?
The following side effects are reported for sotorasib:
- Gastrointestinal: diarrhea (42%), nausea (26%), vomiting (17%), abdominal pain (15%), decreased appetite (13%)
- Increased lab values: aspartate aminotransferase (AST) (39%), alanine aminotransferase (ALT) (38%)
- Hepatic: hepatotoxicity (25%)
- Neuromuscular & Skeletal: musculoskeletal pain (35%), arthralgia (12%)
- Hematologic: lymphocytopenia (48%), anemia (43%), prolonged PTT (23%)
- Respiratory: cough (20%), dyspnea (16%), pneumonia (12%)
- Decreased lab values: calcium (35%), sodium (28%), albumin (22%)
- Cardiovascular: edema (15%)
- Dermatologic: rash (12%)
- Other: increased urinary output (29%), fatigue (26%)
What are the uncommon side effects associated with sotorasib (less than 10%)?
Interstitial pulmonary disease, pneumonitis, respiratory failure, cardiac failure, and gastric ulcer were observed in less than 1 percent.
Are there any important drug interactions I should be aware of?
Sotorasib is a major substrate of CYP3A4 and use with strong CYP3A4 or moderate inducers will decrease sotorasib concentration and effectiveness and should be avoided. Use with strong CYP3A4 inhibitors will increase risk of toxicities with sotorasib and should be avoided.
Sotorasib is also a moderate inducer of CYP3A4 and may decrease concentrations of drugs metabolized via these pathways. Additionally, co-administration with P-gp substrates with a narrow therapeutic index should be avoided.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
There are no recommended dose adjustments for renal impairment, due to lack of patients of these populations in the primary literature.
At treatment initiation, there are no recommended dose adjustments for hepatic impairment. See table below for dosing recommendations in case of hepatotoxicity occurring during treatment.
Grade 2 AST or ALT elevation (>3-5x ULN with symptoms) or
Grade 3 AST or ALT elevation (>5-20x ULN) or
Grade 4 AST or ALT elevation (>20x ULN)
|Hold until ≤ Grade 1, then resume at next lower dose level|
|ALT or AST >3x ULN and bilirubin >2x ULN||Permanently discontinue |
ULN = upper limit of normal
|Sotorasib Dose Reduction Levels |||
|Initial dose||960 mg daily|
|First dose reduction||480 mg daily|
|Second dose reduction||240 mg daily|
|Permanently discontinue if further dose reduction is indicated from 240 mg daily |||
What should my patients know about sotorasib?
- Avoid proton pump inhibitors and H2 receptor antagonists while taking sotorasib. If treatment with an acid-reducing agent can't be avoided, sotorasib should be taken 4 hours before or 10 hours after use of a local acting antacid.
- Contact your provider for new or worsening respiratory symptoms (difficulty breathing, cough, or fever) or liver dysfunction (dark or tea-colored urine, jaundice, nausea/vomiting).
What else should I know about sotorasib?
A comprehensive medication review is recommended at the start of treatment. If a patient is started on new medications it is recommended to evaluate for drug-drug interactions as sotorasib has significant drug interactions with one of the most common CYP pathways, CYP3A4. Additionally, it is recommended to avoid P-gp substrates (ie, digoxin) where minimal concentration changes may lead to serious toxicities.
Hepatotoxicity has been reported with sotorasib and may result in drug-induced liver injury and hepatitis. The median time to first onset of elevate ALT and/or AST was 9 weeks (range: 0.3–42 weeks). Monitor LFTs every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated.
Pulmonary toxicity including interstitial lung disease/pneumonitis occurred rarely on clinical trial. All cases were Grade 3 or 4 at onset and one fatality did occur. The median time to onset was 2 weeks (range: 2-18 weeks).
What useful links are available regarding sotorasib?
Any ongoing clinical trials related to sotorasib?
Trials are ongoing for use of sotorasib in combination with other agents for KRAS-mutated advanced NSCLC following initial first line treatment as well as first line monotherapy use for KRAS-mutated NSCLC patients. More information is available about these clinical trials at https://clinicaltrials.gov.
JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/ Manager, Clinical Pharmacy Services at Washington University School of Medicine, St. Louis, Mo. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.