Home Therapeutic relationship Data presented at ESMO reinforce concern that indicated dose of sotorasib is not optimal

Data presented at ESMO reinforce concern that indicated dose of sotorasib is not optimal


On May 28, 2021, the FDA granted accelerated approval for sotorasib (which had previously received breakthrough designation) for previously treated patients 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 a relationship between dose and efficacy or plasma concentrations.2 So as part of sotorasib’s approval, the FDA issued a post-marketing requirement (PMR) to compare 960 mg to 240 mg daily, and that trial has now completed enrolling patients receiving first-line therapy. (Break Code 201, NCT04933695).3

The FDA explained the reason for this decision in its publicly available review and issued concerns about the failure 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 commended the FDA for its decision to include this PMR.5 We now suggest that full approval be delayed until the outcome of this PMR is available to the FDA.

Results from the Phase III CodeBreak 200 “confirmatory” study of sotorasib 960 mg versus docetaxel in previously treated NSCLC were presented by Melissa Johnson, MD, at the Presidential Symposium of the European Society for Medical Oncology meeting on September 12.6 This phase III trial met its primary endpoint of improvement in 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. In addition, approximately one-third of patients treated with sotorasib, a highly targeted irreversible mutein inhibitor, experienced Grade 3 or higher treatment-related adverse events, 36% of patients requiring dose interruptions, 15% requiring dose reductions and 9% requiring dose discontinuation.

Not only does an overdose cause adverse events that are unrelated to mutant KRAS inhibition, but this overdose could decrease PFS: less can be more.

In our opinion, the intolerance to sotorasib 960 mg reflects an inappropriate dosage, especially with regard to diarrhea, which is attributable to the low bioavailability of this poorly absorbed drug.2 Additionally, 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

Although the toxicities of sotorasib 960 mg daily are less severe than those seen for docetaxel, they are most likely preventable, as previously stated by the FDA. Not only does an overdose cause adverse events that are unrelated to mutant KRAS inhibition, but this overdose could decrease PFS: less can be more.

For example, dose interruption of ibrutinib (another irreversible cysteine-targeting kinase inhibitor) was associated with shorter PFS in chronic lymphocytic leukaemia.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 higher than that of sotorasib 960 mg daily. Given this likely outcome, we suggest that the FDA not grant full approval for the treatment evaluated in CodeBreak 200, and that Amgen suspend initiation of all studies using a 960 mg dose of sotorasib.

A delay in full approval would not impact patient access to the drug and would ensure that CodeBreak 201 results are made public as soon as possible. Additionally, Amgen may 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 of the toxicity of sotorasib 960 mg daily, as seen in CodeBreak 200. Although 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,ten consistent with the median response time in CodeBreak 200. Although we would not expect the clinical effectiveness of 240 mg per day to be less than 960 mg per day, patients who started at a lower dose may be increased if there was no significant toxicity or antitumor effect. Thus, patients could be offered this off-label treatment strategy, pending the results of CodeBreak 201.

The development of sotorasib illustrates the difficulty of optimizing the dose after FDA approval. We reiterate our support for the Optimus project,11 and hope that other sponsors understand the regulatory and market consequences of failing to perform proper pre-market dose optimization.


  1. FDA: FDA approves first targeted therapy for lung cancer mutation previously considered drug-resistant. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug accessed September 20, 2022.
  2. CDER request #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 requiring first-line treatment. https://clinicaltrials.gov/ct2/show/NCT04933695 accessed September 20, 2022.
  4. Shah M, Rahman A, Theoret MR, et al: The conundrum of drug dosing in oncology – When less is more. N Engl J Med 385:1445-1447, 2021
  5. Ratain MJ, Strohbehn GW, Tannock IF, et al: Optimizing the dose: an optimal step forward for the FDA. https://cancerletter.com/guest-editorial/20210611_4/. 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: Phase III CodeBreaK 200 study. ESMO Congress; Presidential Symposium III, 2022
  7. Ivanov SM, Lagunin AA, Filimonov DA, et al: Relationships between 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 drugs with significant hepatic metabolism at higher risk of hepatic adverse effects. Hepatology 51:615-20, 2010
  9. Barr PM, Brown JR, Hillmen P, et al: Impact of ibrutinib dose compliance on therapeutic efficacy in previously treated CLL/LLS patients. 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: Optimus Oncology Center of Excellence Project https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus accessed September 20, 2022.

Disclaimer: Strohbehn is a US federal government employee; the opinions here are his personal opinions and do not reflect those of the US federal government.