Sotorasib: The Poster Child for Project Optimus – Truths and Fantasies

Targeted therapies have become increasingly important in oncology in recent years, with advances in this field transforming cancer treatment. At the forefront is a targeted treatment developed against the KRAS G12C mutation: sotorasib (Lumakras, Amgen). KRAS is among the most common genetic mutations in cancer, and this mutation is detected particularly in patients with non-small cell lung cancer (NSCLC), affecting approximately 13% of these patients. For many years, KRAS mutations were considered “untreatable,” but the development of sotorasib changed that perception.

In May 2021, sotorasib received accelerated approval from the Food and Drug Administration (FDA) in the United States for treating KRAS G12C-mutated NSCLC. This made it the first approved treatment for patients with this specific mutation and was considered a major advance in oncology. However, the development was followed by debate over determining the optimal dose and balancing treatment effectiveness against toxicity.

The Debate Over the Optimal Dose

The article by Dr. Garth Strohbehn, Dr. Allen Lichter, and Dr. Mark Ratain, “Sotorasib, the Poster Child for Project Optimus: Truths and Fantasies”, is central to this debate, arguing that targeted oncology treatments should seek the “optimal dose” rather than the maximum tolerated dose (MTD). The authors state that sotorasib's development and FDA approval process marked the beginning of a new era in oncology and provide a vivid example of ongoing discussions about dose optimization. The remainder of this article contains a translation of their important commentary.

In January 2021, we wrote in these pages that targeted oncology therapies should move away from identifying and using the maximum tolerated dose (MTD) and instead seek the “optimal dose,” which best balances efficacy and toxicity. The newly identified KRAS G12C inhibitor sotorasib illustrated the MTD problem. Although responses were seen at lower doses, its phase I trial was designed to find a dose causing toxicity in 25% to 30% of participants. The blood concentration area-under-the-curve values at 960 mg and 240 mg were identical, and oral doses above 240 mg did not get more drug into the circulation. Excess drug simply passed through the gastrointestinal tract, potentially causing unnecessary side effects. We had called on the FDA to require testing at lower doses.

In May 2021, the FDA granted accelerated approval to sotorasib at 960 mg for KRAS G12C-mutated NSCLC, but required several postmarketing trials, including a dose-ranging trial comparing 960 mg with 240 mg and a phase III confirmatory trial comparing sotorasib with docetaxel. The FDA also announced Project Optimus, a regulatory framework requiring all new oncology drugs to undergo a formal dose-response study to select the optimal dose for registration trials. The era of seeking the MTD and carrying that dose forward was over.

What has happened to sotorasib over the past 3 years? Are we closer to understanding its optimal dose? Let us examine the data.

The Dose-Ranging Study

The FDA-required dose-ranging study compared 960 mg with 240 mg, enrolled 209 participants, was completed in 2022, and reported its results in autumn 2023. Although there was a trend toward better outcomes at 960 mg, no efficacy measure showed a statistically significant improvement. Median overall survival was 13.0 months at 960 mg and 11.7 months at 240 mg, without a statistically significant difference. Progression-free survival, the primary endpoint in the phase III trial, was identical in both arms.

As expected, the incidence of grade 3 treatment-related adverse events increased substantially at the higher dose (35.6% versus 19.2%), often leading to dose reduction or treatment interruption (39.4% versus 22.1%). Despite increased toxicity without benefit, the sponsor and principal investigator claim that the study established the higher dose's superiority. An objective examination of the data, however, makes it impossible to conclude that 960 mg is a better option.

The Phase III Confirmatory Trial

The phase III study had its own well-documented problems. It randomly assigned 345 participants with advanced NSCLC that had progressed on platinum-based chemotherapy and a checkpoint inhibitor to receive either 960 mg of sotorasib or docetaxel. Median progression-free survival was 5.6 versus 4.5 months, favoring sotorasib, with a hazard ratio of 0.66. Case closed? Is sotorasib superior to docetaxel in this population?

Not so fast. During its review, the FDA identified asymmetric early dropout, with more participants leaving the docetaxel arm. This raised concerns that investigators' assessments of progressive disease biased the trial in favor of sotorasib by enabling crossover from docetaxel before blinded central assessments of disease progression. To review the results and determine the next regulatory steps, the FDA convened its Oncologic Drugs Advisory Committee (ODAC), an independent third party comprising oncologists, statisticians, and patient advocates. After hearing nearly 8 hours of arguments from the sponsor and the FDA, ODAC concluded that these conduct issues had irreparably biased the results, making them “uninterpretable.”

Because the sponsor's studies to date provide no clear evidence that the higher dose is necessary, it has resorted to selecting evidence supporting its claim, burying pharmacokinetic data in article supplements, and using press releases and websites without context to promote the higher dose.

Ultimately, however, we believe that oncologists, as a community seeking to improve patients' well-being through the scientific method, must adhere closely to the primary data. We also urge the FDA to act as soon as possible to prevent patients with KRAS-mutated cancer from receiving an unnecessarily toxic dose of an important drug.

Authors' Postscript: As this article went to press, sotorasib's sponsor issued a press release reporting that it had received a complete response letter from the FDA. In the letter, the FDA (1) rejected supplemental new drug approval for sotorasib as second-line treatment of NSCLC, (2) issued a postmarketing requirement to repeat the confirmatory trial (design not yet known), and (3) allowed the labeled dose to remain 960 mg going forward. Although we agree with decisions (1) and (2), we believe that the scientific evidence continues to support the 240 mg dose, and we recommend that oncologists prescribe 240 mg off-label.

In this situation, the FDA may lack the authority to change the labeled dose before full regulatory approval. The alternative of withdrawing the drug entirely from the market was probably considered and rejected. Given the pharmaceutical industry's history of selectively reporting the contents of nonpublic complete response letters, and their exemption from Freedom of Information Act requests, this situation should renew efforts to improve transparency in FDA decision-making. In light of the new postmarketing requirement and the public health imperative to provide the safest drugs to patients with KRAS G12C-mutated NSCLC, we call on the sponsor to publish the complete response letter in full so that oncologists and patients can make fully informed decisions.