|
| |
 |
|
| DRUG REVIEW |
|
| Year : 2021 | Volume
: 4
| Issue : 3 | Page : 524-528 |
|
Sotorasib – an inhibitor of KRAS p.G12c mutation in advanced non-small cell carcinoma: A narrative drug review
Amit Kumar Agrawal, Ramya Pragya, Amit Choudhary, Anuj Gupta, Kuraparthy Sambasivaiah, Bal Krishna Mishra, Satvik Khaddar, Akhil Kapoor
Department of Medical Oncology, Mahamana Pandit Madan Mohan Malviya Cancer Centre, and Homi Bhabha Cancer Hospital, Tata Memorial Centre, Varanasi, Uttar Pradesh, India
| Date of Submission | 18-Jun-2021 |
| Date of Decision | 18-Aug-2021 |
| Date of Acceptance | 16-Sep-2021 |
| Date of Web Publication | 08-Oct-2021 |
Correspondence Address:
Akhil Kapoor
Department of Medical Oncology, Mahamana Pandit Madan Mohan Malviya Cancer Center, and Homi Bhabha Cancer Hospital (A Unit of Tata Memorial Center, Mumbai), Varanasi, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/crst.crst_145_21
The KRAS p.G12C mutation occurs in seen in 13% of non-small cell lung cancers (NSCLCs) and in approximately 1%–3% of colorectal and other cancers. Until the last decade, there were no approved therapies for targeting the KRAS mutation, but recently, drugs targeting the mutation have been discovered. KRAS is a small protein structurally without any deep pockets making it almost impossible to target. Furthermore, it binds in its active state with the GTP protein, with remarkably close affinity making blockage of the KRAS mutation challenging. Sotorasib is a nanomolecule that selectively and irreversibly targets the KRAS mutation. The phase 2 trial (CodeBreaK100) conducted in a total of 129 patients with advanced solid tumors harboring the KRAS p.G12C mutation showed anticancer activity in patients following multiple lines of treatment. We searched for the articles published online between 2018 and May 2021 with keywords, “KRAS mutation,” “lung cancer,” and “sotorasib.” In this review article, we have discussed the history, pharmacokinetics, dosing, important studies, toxicities, and other pertinent details of sotorasib.
Keywords: Non-small cell lung cancer, sotorasib, KRAS, G12C, precision medicine, targeted
How to cite this article:
Agrawal AK, Pragya R, Choudhary A, Gupta A, Sambasivaiah K, Mishra BK, Khaddar S, Kapoor A. Sotorasib – an inhibitor of KRAS p.G12c mutation in advanced non-small cell carcinoma: A narrative drug review. Cancer Res Stat Treat 2021;4:524-8 |
How to cite this URL:
Agrawal AK, Pragya R, Choudhary A, Gupta A, Sambasivaiah K, Mishra BK, Khaddar S, Kapoor A. Sotorasib – an inhibitor of KRAS p.G12c mutation in advanced non-small cell carcinoma: A narrative drug review. Cancer Res Stat Treat [serial online] 2021 [cited 2022 May 24];4:524-8. Available from: https://www.crstonline.com/text.asp?2021/4/3/524/327759 |
| Introduction | |  |
The RAS oncogene (rat sarcoma viral oncogene homolog) is one of the most common oncogenes in humans and nearly 27% of human carcinomas have been noted to harbor active RAS mutations.[1] There are three basic human RAS genes – NRAS (neuroblastoma RAS viral oncogene homolog), HRAS (Harvey rat sarcoma viral oncogene homolog), and KRAS (Kirsten rat sarcoma viral oncogene homolog). In a normal cell, their function results in controlled cell growth. These genes produce the respective proteins (NRAS, HRAS, KRAS) and these proteins by controlling various signaling pathways (like the MAP kinase pathway, PI3K/AKT/mTOR pathway) regulate cell processes such as proliferation, differentiation, adhesion, and apoptosis. However, their mutation results in the loss of GTPase function, resulting in constitutive activation of their downstream pathways, leading to the development of cancer and progression.[2]
In general, carcinomas of the colon, pancreas, and lung have been noted to harbor mutations of KRAS, bladder tumors have HRAS mutations, and NRAS mutations are seen in hematopoietic neoplasms.[3] The frequency of the RAS mutation varies in different tumors and different datasets. KRAS mutation has been noted in 30%–50% of patients with colorectal cancer,[4] 75%–98% of patients with pancreatic cancers,[3] 12%–36% of lung adenocarcinomas,[5] and 1%–16% of small cell lung cancers.[3],[4],[5] HRAS mutation has been found in 0%–84% and NRAS mutations in 0%–80% of patients with bladder cancers.[4],[5] Overall, among these three oncogenes, KRAS mutations are most commonly seen in human cancers (up to 25% of all human cancers).[6] In patients with non-small cell lung cancer (NSCLC), the KRAS mutation most commonly occurs on exon 2 at codon 12, followed less commonly by codon 13 (3%–5%) and rarely (<1%), at exon 3 of codon 61.[7] The KRAS p.G12C mutation occurs in approximately 13% of NSCLCs and in 1%–3% of colorectal cancers and other solid cancers.[8] Various studies have shown that patients with KRAS-mutant cancers have a poor response to standard anticancer therapies.[9],[10],[11],[12] Inhibition of KRAS could be one of the potential treatment strategies for these tumors. Sotorasib is a novel drug with the potential of exclusively targeting the KRAS p.G12C mutation. In this review, we will briefly discuss the development of this drug, its mechanism of action, key clinical trials related to it, and current clinical indications.
| Methods | | |
We thoroughly searched the PubMed database and the proceedings of various meetings including the annual meetings of the American Society of Clinical Oncology and the European Society for Medical Oncology. The methodology used is outlined in [Figure 1]. | Figure 1: The search strategy for the literature search for the sotorasib drug review (Acronyms: ASCO-American Society of Clinical Oncology; ESMO: European Society of Medical Oncology)
Click here to view |
Sotorasib
Chemical structure and drug class
Sotorasib originally named as AMG-510 is an acrylamide-derived covalent inhibitor of KRAS G12C.[13] Its molecular formula is C30H30F2N6O3 with a molecular weight of 560.6 g/mol.[14]
Mechanism of action
Sotorasib is an irreversible and specific inhibitor of KRAS G12C. This specific mutation basically entails a change of glycine to cysteine at position 12, resulting in the constitutive activation of KRAS.[15] This mutated cysteine lies next to a pocket (P2) in the protein and sotorasib by its unique interaction with the P2 pocket inhibits the KRAS protein. This P2 pocket is present only in the inactive GDP-bound conformation of KRAS and its binding with sotorasib results in the trapping of the RAS protein in its inactive from.[16]
Dosing and administration
Sotorasib is available as 120 mg tablets. The recommended dose is 960 mg once daily with or without food. The first dose reduction is to 480 mg if grade 3/4 toxicities occur such as transaminitis, nausea/vomiting, or diarrhea and the second dose reduction is to 240 mg if grade 3/4 toxicities recur following the first dose reduction.[14]
Metabolism and clearance
Sotorasib is predominantly metabolized through non-enzymatic conjugation and oxidative metabolism by the cytochrome system, specifically CYP3As. It is mostly eliminated in the feces; a small fraction is also eliminated in the urine.[14]
Toxicity
Diarrhea (all grades: 43%, grade 3/4 : 5%), fatigue (all grades: 26%, grade 3/4: 2%), nausea and vomiting (all grades: 26%; grade 3/4: 2%), abdominal pain and reduced appetite (all grades: 15%, grade 3/4 : 2%), dyspnea (all grades: 20%, grade 3/4 : 1.5%) and cough (all grades: 16%, grade 3/4 : 2.9%), back pain (all grades: 35% grade 3/4 : 8%), increase in the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (all grades: 25%, grade 3/4 ; 12%), and lymphopenia (all grades: 48%, grade 3/4 : 2%).[14]
Special considerations and dose modifications
The Food and Drug Administration (FDA) recommends monitoring of the liver function tests every 3 weeks for the initial 3 months and then once a month, as clinically indicated, in patients who have been started on sotorasib. If a patient develops grade 2 transaminitis and is symptomatic or if there is grade 3 or grade 4 transaminitis, sotorasib should be withheld until recovery to less than Grade 1 or baseline. After recovery of the hepatic transaminases, sotorasib should be resumed at one lower dose level. However, if the AST or ALT levels are elevated to more than 3 times the upper limit of normal (ULN) along with a rise in the bilirubin to more than 2 times the ULN, sotorasib should be permanently discontinued. In case interstitial lung disease or pneumonitis is suspected, sotorasib should be withheld; it should be permanently discontinued in case the diagnosis of interstitial lung disease is confirmed.[14]
Drug interactions
There are no absolute contraindications to using sotorasib with any drug.[14] However, a few important interactions which are relevant to clinical practice are mentioned below:
- Oral pantoprazole: Pantoprazole is known to decrease the level or effect of sotorasib by inhibition of gastrointestinal absorption. If the use of an acid-reducing agent cannot be avoided, administer sotorasib 4 hours before or 10 hours after the administration of a locally acting antacid[14]
- Apixaban: Sotorasib can decrease the level or effect of apixaban by means of the p-glycoprotein (MDR1) efflux transporter. The use of an alternative is suggested, if feasible[14]
- Fentanyl: Sotorasib is known to decrease the level of fentanyl by affecting the hepatic/intestinal enzyme CYP3A4 metabolism. The use of an alternative is suggested, if feasible.[14]
Pregnancy and lactation
There are no human data available for the use of sotorasib in pregnancy and lactation. In animal studies, sotorasib did not cause embryotoxicity or fetal maldevelopment.
Key clinical trials of sotorasib
CodeBreaK100 is the only completed human clinical trial evaluating the use of sotorasib. It is a phase I/II study with various cohorts; the phase I part of this trial has shown promising activity of sotorasib in patients with NSCLC, although clinical activity was also observed in other KRAS G12C mutant tumors. [Table 1] shows the results of various cohorts of this study that have been reported so far; of note, the trial continues to recruit patients and the reported results are part of the interim analyses only.
Indications and the FDA approval status of sotorasib
Sotorasib was granted priority review designation by the FDA on February 16, 2021, for the treatment of patients with KRAS G12C-mutated locally advanced or metastatic NSCLC. Based on the results of the NSCLC cohort of the CodeBreaK100 trial, it was given accelerated approval for the KRAS G12C-mutant NSCLC patients who have been treated with at least one prior line of systemic therapy.[14] The accelerated approval of sotorasib was exciting, because of the fact that this drug has shown efficacy in a treatment-refractory population (those who had received multiple prior lines of treatment), although the approval came along with a rider that stated that the company must carry out additional trials to prove the efficacy and safety of sotorasib.
Molecular predictors of response
In the CodeBreaK100 trial itself, there were different response rates of sotorasib noted in different tumors, thus again highlighting the biological diversity even in similar KRAS-mutated tumors[17] and the presence of other genetic drivers that play a role in cell proliferation. Co-occurring mutations such as KRAS-STK11 and KRAS-KEAP1 are associated with poor outcomes in KRAS-mutant NSCLC patients.[19],[20] We know that based upon translational and proteomic data, KRAS-mutant NSCLC tumors have been classified into three subgroups – those with concomitant TP53 mutations, KP; the second group with the inactivating mutation in the tumor suppressor liver kinase b1 (LKB1) labeled as KL; and the third with deletion of 2 tumor suppressor genes, i.e., CDKN2A and CDKN2B labeled as KC.[18] These three subgroups have been known to have differential sensitivities to chemotherapy and immunotherapy. However, the effect of these coexistent mutations or other markers like the tumor mutation burden on the response to KRAS inhibitors is still not explored in human clinical trials.
Further ongoing trials
CodeBreaK100 trial, which is a phase I/II study with objectives to evaluate the safety, dose finding and cohort expansion, is still recruiting participants and will provide us with a better understanding about the responses of sotorasib in other tumors as well. Besides, other trials are ongoing and/or scheduled to evaluate the safety and efficacy of sotorasib alone or in combination with other anticancer agents in previously treated as well as treatment-naïve patients. [Table 2] describes the current ongoing trials related to sotorasib.
Other KRAS inhibitors
Apart from sotorasib, another selective KRAS G12C inhibitor is adagrasib (MRTX849). Based on the results of the phase I/II KRYSTAL-1 study, the FDA has granted accelerated approval for this agent for the treatment of patients with previously treated (with chemotherapy and/or immunotherapy) KRAS G12C-mutant NSCLC.[25],[26] [Table 3] describes the salient features of sotorasib.
Limitations
Despite showing good clinical activity among patients with KRAS G12C-mutated NSCLC, there are some limitations to this molecule. Sotorasib is ineffective against other KRAS mutations. The responses in tumors other than NSCLC do not look promising as of now. There is a lack of predictive markers for differential response, and at present, the long-term safety and efficacy are unknown when used in combination with other drugs.
| Interpretation and conclusion | | |
KRAS-mutant tumors, which have been historically considered to be poor responders to standard anticancer therapies, constitute a significant proportion of tumors such as NSCLC and colorectal cancer. There is an unmet need to develop newer targeted agents to improve the outcomes. Among the spectrum of the different KRAS mutations, KRAS G12C is seen in more than 10% of NSCLCs, and studies have shown the safety and efficacy of targeted agents for these patients. Sotorasib, an inhibitor of KRAS G12C, was shown to be clinically effective in a phase II trial, and approved by the FDA for patients with locally advanced or metastatic NSCLC patients harboring KRAS G12C mutation. Trials evaluating sotorasib as monotherapy or in combination with various agents in patients with NSCLC or other solid tumors are ongoing.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Cox AD, Der CJ. Ras history: The saga continues. Small GTPases 2010;1:2-27.  |
| 2. | O'Bryan JP. Pharmacological targeting of RAS: Recent success with direct inhibitors. Pharmacol Res 2019;139:503-11. |
| 3. | Beganovic S. Clinical significance of the KRAS mutation. Bosn J Basic Med Sci 2009;9 Suppl 1:17-20. |
| 4. | Chatterjee K, Mukherjee P, Hoque J, Das M, Saha S. Extended RAS mutations (KRAS and NRAS) in patients with colorectal cancers in eastern India: An observational study. Cancer Res Stat Treat 2021;4:244-50. [Full text] |
| 5. | Kodaz H, Kostek O, Hacioglu MB, Erdogan B, Kodaz CE, Hacibekiroglu I, et al. Frequency of RAS mutations (KRAS, NRAS, HRAS) in human solid cancer. Breast Cancer 2017;7:1-7. |
| 6. | Kranenburg O. The KRAS oncogene: Past, present, and future. Biochim Biophys Acta 2005;1756:81-2. |
| 7. | Tímár J. The clinical relevance of KRAS gene mutation in non-small-cell lung cancer. Curr Opin Oncol 2014;26:138-44. |
| 8. | Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 2020;383:1207-17. |
| 9. | Massarelli E, Varella-Garcia M, Tang X, Xavier AC, Ozburn NC, Liu DD, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res 2007;13:2890-6. |
| 10. | Tsao MS, Aviel-Ronen S, Ding K, Lau D, Liu N, Sakurada A, et al. Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non-small-cell lung cancer. J Clin Oncol 2007;25:5240-7. |
| 11. | Zalcman G, Beau-Faller M, Creveuil C, de Fraipont F, Mounawar M, Richard N, et al. Use of Ras effector RASSF1A promoter gene methylation and chromosome 9p loss of heterozygosity (LOH) to predict progression-free survival (PFS) in perioperative chemotherapy (CT) phase III trial IFCT-0002 in resectable non-small cell lung cancer. J Clin Oncol 2008;26:7500. |
| 12. | Hames ML, Chen H, Iams W, Aston J, Lovly CM, Horn L. Correlation between KRAS mutation status and response to chemotherapy in patients with advanced non-small cell lung cancer☆. Lung Cancer 2016;92:29-34. |
| 13. | Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS (G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 2019;575:217-23. |
| 14. | |
| 15. | Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013;503:548-51. |
| 16. | Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 2016;351:604-8. |
| 17. | Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 2021;384:2371-81. |
| 18. | Hong DS, Kuo J, Sacher AG, Barlesi F, Besse B, Kuboki Y, et al. CodeBreak 100: Phase I study of AMG 510, a novel KRASG12C inhibitor, in patients (pts) with advanced solid tumors other than non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). J Clin Oncol 2020;38:3511. |
| 19. | Ferrer I, Zugazagoitia J, Herbertz S, John W, Paz-Ares L, Schmid-Bindert G. KRAS-Mutant non-small cell lung cancer: From biology to therapy. Lung Cancer 2018;124:53-64. |
| 20. | Skoulidis F, Byers LA, Diao L, Papadimitrakopoulou VA, Tong P, Izzo J, et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 2015;5:860-77. |
| 21. | |
| 22. | |
| 23. | |
| 24. | |
| 25. | Riely GJ, Ou SI, Rybkin I, Spira A, Papadopoulos K, Sabari JK, et al. 99O_PR KRYSTAL-1: Activity and preliminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in patients (Pts) with advanced non–small cell lung cancer (NSCLC) harboring KRASG12C mutation. J Thoracic Oncol 2021;16:S751-2. |
| 26. | Batra U, Nathany S. Biomarker series: KRAS - A narrative review. Cancer Res Stat Treat 2021;4:516-23. [Full text] |
[Figure 1]
[Table 1], [Table 2], [Table 3]
|
Search Pubmed for