Data presented at ESMO strengthens concern that the labeled dose of sotorasib is not optimal

On May 28, 2021, the FDA granted an accelerated approval for sotorasib (which had previously received Breakthrough designation) for previously treated KRAS G12C non-small cell lung cancer (NSCLC) at a dose of 960 mg daily.¹ 

However, the FDA indicated that the approved dose was unlikely to be appropriate, given the lack of any relationship between dose and efficacy or plasma concentrations.² Thus, in the context of the approval of sotorasib, the FDA issued a post-marketing requirement (PMR) to compare 960 mg to 240 mg daily, and that trial has now completed enrollment of patients receiving first-line treatment (Code Break 201, NCT04933695).³ 

The FDA articulated the reason for this decision in its publicly available review, and published concerns about failures to conduct dose optimization studies of new agents in The New England Journal of Medicine.⁴ 

In the June 11, 2021, issue of this publication, we congratulated the FDA on its decision to include this PMR.⁵ We now suggest that full approval should be delayed until the result of this PMR is available to FDA. 

The results of the “confirmatory” CodeBreak 200 phase III study of sotorasib 960 mg versus docetaxel in previously treated NSCLC were presented by Melissa Johnson, MD, in the Presidential Symposium of the meeting of the European Society of Medical Oncology on Sept. 12.⁶ This phase III trial met its primary endpoint of improving progression-free survival (PFS), with a hazard ratio of 0.66, but with only a 1.1 month increase in median PFS (5.6 versus 4.5 months). 

There was also no improvement in overall survival. Furthermore, approximately one-third of patients treated with sotorasib, an exquisitely targeted irreversible mutein inhibitor, experienced grade 3 or higher treatment-related adverse events, with 36% of patients requiring dose interruptions, 15% requiring dose reductions, and 9% requiring dose discontinuation. 

Not only does excessive dosing result in adverse events that are unrelated to inhibition of mutant KRAS, but this excessive dosage might decrease PFS: less may be more.

In our opinion, the intolerance to sotorasib 960 mg reflects inappropriate dosing, particularly regarding diarrhea, which is attributable to the low bioavailability of this poorly absorbed drug.² In addition, hepatotoxicity developed in >10% of patients, which would be predicted for the very high administered dose of this extensively metabolized drug and would also be predicted to be less severe at lower doses.^7,8

While the toxicities of sotorasib 960 mg daily are less severe than were observed for docetaxel, they are most likely avoidable, as has been already articulated by the FDA. Not only does excessive dosing result in adverse events that are unrelated to inhibition of mutant KRAS, but this excessive dosage might decrease PFS: less may be more. 

For example, dose interruption of ibrutinib (another cysteine-targeted irreversible kinase inhibitor) was associated with shorter PFS in chronic lymphocytic leukemia.⁹ Thus, a trial comparing sotorasib 240 mg (or less) to docetaxel might show more favorable results (for sotorasib) than the CodeBreak 200 study.

It is highly likely that CodeBreak 201 will show that the therapeutic index of sotorasib 240 mg daily is superior to that of sotorasib 960 mg daily. Given this probable result, we suggest that the FDA should not grant full approval for the treatment evaluated in CodeBreak 200, and that Amgen should pause initiation of all studies using a sotorasib dose of 960 mg. 

A deferral of full approval would not impact patient access to the drug and would ensure that the results of CodeBreak 201 are made public as soon as possible. Furthermore, Amgen could still pursue combination studies using a daily dose of 240 mg.

What should prescribers do now? While many will continue to treat patients according to the current label, prescribers should consider other options. First, patients should be informed regarding the toxicity of sotorasib 960 mg daily as observed in CodeBreak 200. While we are not suggesting that patients would prefer chemotherapy with docetaxel, some patients may prefer to start with a lower dose of sotorasib, 240 mg daily as used in the CodeBreak 201 study. 

In the phase I trial, patients treated with 180 mg daily responded after 6 weeks,¹⁰ consistent with the median time to respond in CodeBreak 200. While we do not expect the clinical efficacy of 240 mg daily to be inferior to 960 mg daily, patients started at a lower dose could be escalated if there were neither significant toxicity nor an antitumor effect. Thus, patients could be offered this off-label treatment strategy, while we await the CodeBreak 201 results.

The development of sotorasib illustrates the difficulty of optimizing the dose after FDA approval. We reiterate our support for Project Optimus,¹¹ and hope that other sponsors understand the regulatory and commercial consequences of failure to conduct appropriate pre-marketing dose optimization.

References

1. FDA: FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug accessed 20 September 2022. 
2. CDER Application #214665Orig1s000 sotorasib https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214665Orig1s000MultidisciplineR.pdf accessed September 20, 2022. 
3. NIH NLM Clinical Trials.gov. A Study of Sotorasib (AMG 510) in Participants With Stage IV NSCLC Whose Tumors Harbor a KRAS p.G12C Mutation in Need of First-line Treatment. https://clinicaltrials.gov/ct2/show/NCT04933695 accessed 20 September 2022. 
4. Shah M, Rahman A, Theoret MR, et al: The Drug-Dosing Conundrum in Oncology – When Less Is More. N Engl J Med 385:1445-1447, 2021
5. Ratain MJ, Strohbehn GW, Tannock IF, et al: Optimize the dose: an optimal step forward for FDA. https://cancerletter.com/guest-editorial/20210611_4/. The Cancer Letter 47, 2021
6. Johnson ML, De Langen J, Waterhouse DM, et al: LBA10 – Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. ESMO Congress; Presidential Symposium III, 2022
7. Ivanov SM, Lagunin AA, Filimonov DA, et al: Relationships between the Structure and Severe Drug-Induced Liver Injury for Low, Medium, and High Doses of Drugs. American Chemical Society 35:402-411, 2022
8. Lammert C, Bjornsson E, Niklasson A, et al: Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology 51:615-20, 2010
9. Barr PM, Brown JR, Hillmen P, et al: Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood 129:2612-2615, 2017
10. Hong DS, Fakih MG, Strickler JH, et al: KRAS(G12C) Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med 383:1207-1217, 2020
11. FDA: Oncology Center of Excellence Project Optimus https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus accessed September 20, 2022. 

Disclaimer: Strohbehn is an employee of the U.S. federal government; the views here are his personal views and do not reflect those of the U.S. federal government.