FDA ODAC Panel Votes Against Sotorasib Data in KRAS G12C+ Advanced NSCLC


The FDA Oncologic Drugs Advisory Committee voted 10-to-2 that findings from the phase 3 CodeBreaK 200 trial cannot be reliably interpreted.

FDA ODAC Panel Votes Against Sotorasib Data in KRAS G12C+ Advanced NSCLC

FDA ODAC Panel Votes Against Sotorasib Data in KRAS G12C+ Advanced NSCLC

According to the FDA’s Oncologic Drugs Advisory Committee (ODAC), the progression-free survival (PFS) data from the phase 3 CodeBreaK 200 trial (NCT04303780) evaluating sotorasib (Lumakras) vs docetaxel for the treatment of patients with pretreated, locally advanced or metastatic KRAS G12C–mutated non–small cell lung cancer (NSCLC) cannot be reliably interpreted.

The panel recently held a vote, in which participants voted 10-to-2 against the reliability of the results.

“I voted no. No one expects a perfect randomized clinical trial, but what we hope for is a small number of issues in trial conduct, and [we hope the trial is] large enough to withstand the uncertainties caused by those sorts of issues,” said Mark R. Conaway, PhD, a professor in the Division of Translational Research and Applied Statistics Department of Public Health Sciences at the University of Virginia School of Medicine. “For [CodeBreaK 200], we seemed to have the opposite [outcome]: a large number of issues that cloud the interpretation of a small observed [PFS] effect.”

During the meeting, the committee outlined several points of potential bias during the study and statistical analysis, including asymmetric early dropouts between the treatment arms, investigator imaging assessments favoring sotorasib, and early crossover per investigator assessment affecting BICR assessments.2

In the control arm, 13% of patients (n = 23) withdrew consent and were censored at day 1 for not having a post-baseline assessment compared with 1% of patients (n = 2) in the sotorasib arm. The censorship of patients who dropped out could lead to an overestimation of PFS if withdrawn patients would have had better outcomes.

Study protocol was also amended to include a crossover option for patients in the docetaxel arm after efficacy data for sotorasib were reported from the phase 2 CodeBreaK 100 trial (NCT03600883). However, the crossover amendment was implemented after 99% of patients had been enrolled on CodeBreaK 200.

“The question before the committee today was not one of the efficacy of sotorasib in lung cancer. Rather, specifically, [the question surrounded] the ability to interpret data from a relatively small clinical trial conducted with a highly anticipated agent in a hyper-information age where both patients and providers had high expectations,” Ravi A. Madan, MD, a senior clinician at the National Cancer Institute, said following the vote.1 “Given that we had powers of statistical permutations discussed that could change interpretations, I had to vote no on the reliability of the PFS benefit for this study. The factors that contributed to the lack of certainty come from the small size [of the trial], investigator conduct, and the small 5-week PFS benefit. I do think if the PFS benefit were greater, this would have been a much shorter conversation.”

Topline results from the CodeBreak 200 showed that patients in the sotorasib arm (n = 171) experienced a median PFS of 5.6 months compared with 4.5 months for docetaxel (HR, 0.66; 95% CI, 0.51-0.86).2 The committee noted that although there was an approximate 5-week difference in PFS between the arms, imaging to evaluate for progression occurred once every 6 weeks, leaving a potential margin of error for when progression occurred. Furthermore, the median follow-up was 15.2 months for the sotorasib arm vs 6.9 months for the docetaxel arm.

Jeevan Puthiamadathil, MD, a clinical reviewer for the FDA who did not participate in the ODAC vote, explained that the initial separation of the PFS curves decreased over time, converging at approximately 7 months, and following additional separation, they again merged at around 15 months. He also noted that relatively few censored patients remained in follow-up at 7 months, pointing to a potential lack of reliability in interpreting the PFS curves at this point.

“I voted yes because the study met its primary end point, based on the intent-to-treat analysis,” Jorge Nieva, MD, an associate professor of clinical medicine at the Keck School of Medicine at the University of Southern California, said.1 “Ultimately, we have to take the statistical plan as it is written and analyze things according to what was planned. The post hoc analyses are informative, but [they] ultimately don’t change the benefits that were, in fact, observed. I don’t think a type 1 error occurred here. Given the corroborating evidence, I have confidence that [sotorasib] does have a PFS benefit over [docetaxel] in this case.”

However, Nieva added that he was concerned with the quality of the BICR and the variation that occurred between the first and second interpretations of the PFS data, noting that the data and applicant should be subject to greater auditing.

In May 2021, In May 2021, the FDA granted accelerated approval to sotorasib, locally advanced or metastatic NSCLC, as determined by an FDA‑approved test, who received at least 1 prior systemic therapy.3

Accelerated approval was supported by data from the phase 2 CodeBreaK 100 trial. Findings showed that sotorasib elicited an objective response rate of 36% (95% CI, 28%-45%) in patients with KRAS G12C–mutated NSCLC who had progressed following treatment with an immunotherapy and/or chemotherapy. Additionally, patients achieved a median duration of response (DOR) of 10 months, and 58% of patients experienced a DOR of at least 6 months. Notably, the disease control rate was 81% (95% CI, 73%-87%).

The phase 3 CodeBreaK 200 was intended as a confirmatory study following the accelerated approval of sotorasib.2 It enrolled patients with KRAS G12C–mutated advanced or metastatic NSCLC who received at least 1 prior line of therapy including chemotherapy and an immune-oncology agent. Patients were randomly assigned 1:1 to receive 960 mg of oral sotorasib per day or 75 mg/m2 of docetaxel once every 3 weeks. Patients in the control arm were permitted to cross over to receive 960 mg of sotorasib once per day upon disease progression.

PFS per BICR served as the trial’s primary end point. Secondary end points included overall survival, overall response rate, and duration of response.


  1. Oncologic Drugs Advisory Committee Meeting. FDA. October 5, 2023. Accessed October 5, 2023. https://www.youtube.com/watch?v=yH0mGVt1fP4
  2. Sotorasib for KRAS G12C mutated locally advanced or metastatic nonsquamous non-small cell lung cancer. FDA. October 5, 2023. Accessed October 5, 2023. https://www.fda.gov/media/172756/download
  3. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. News release. FDA. May 28, 2021. Accessed October 5, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc
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