NEW YORK – The US Food and Drug Administration's Office of Prescription Drug Promotion (OPDP) last week sent an untitled letter to Mirati Therapeutics and Bristol Myers Squibb regarding misleading claims about the efficacy of the KRAS G12C inhibitor Krazati (adagrasib) on its healthcare provider website.
The OPDP cited several such claims — including ones describing the drug's disease control rate and survival outcomes — on the website where BMS described the efficacy of Krazati in KRAS G12C-mutant locally advanced or metastatic non-small cell lung cancer, as demonstrated in the Phase I/II KRYSTAL-1 trial. The agency noted in the letter that it received multiple complaints about the website through the FDA's Bad Ad program, which aims to help healthcare providers recognize and report misleading prescription drug promotions.
The company claims on the website that the disease control rate on Krazati is 80 percent and that 80 percent of patients experienced tumor shrinkage of any magnitude in the KRYSTAL-1 trial. However, the OPDP said in the letter that data is misleading because it suggests that Krazati improves the disease control rate and depth of response based on composite data of stable disease, partial response, or complete response when the trial was not designed to evaluate this. OPDP noted that because KRYSTAL-1 was a single-arm trial, it "did not establish that the stable disease result was attributable to the effect of the drug; for example, the result may instead reflect the natural history of the disease."
OPDP similarly cited the limitations of the single-arm KRYSTAL-1 trial in BMS's representation of overall and progression-free survival on the Krazati website. The agency said that Krazati was granted accelerated approval based on overall response rate and duration of response endpoints, but that survival endpoints are typically "uninterpretable" in a single arm trial.
The agency noted that BMS included text alongside the survival data saying that single-arm trials do not adequately characterize time-to-event endpoints such as overall and progression-free survival, but that this disclosure did not correct the misrepresentation of the survival data.
"Evaluation of time-to-event endpoints requires randomized controlled trials because a comparator arm is necessary to assess whether the effect seen on the endpoint being studied is attributable to the drug or some other factor," OPDP wrote in the letter. "Thus, these claims are misleading because they are based on the results of a trial that is not capable of producing interpretable OS and PFS results."
The OPDP said that BMS overstated the duration of response of Krazati. On the website, it states the median duration of response was 12.5 months based on KRYSTAL-1; however, the previously reported median duration of response was 8.5 months. BMS cited "pooled data" to support the 12.5 months result, but OPDP said the FDA was not able to verify this claim and was not aware of this data.
Finally, the OPDP said the claims about intracranial response were misleading because the cited post hoc analyses for this data do not establish that Krazati is effective for treating brain metastases. It noted that the typical information to measure intracranial response — which includes how the brain lesions were previously treated — was not collected in the single-arm trial.
The agency said the only data known about the patients included in the intracranial response cohort is that the majority were previously treated with radiation therapy for brain metastases. "This post hoc analysis did not establish that improvement in intracranial [overall response rate] is attributable to treatment with Krazati; these results may instead represent the effects of radiation therapy," OPDP wrote.
While BMS does include text that this intracranial response data was from a post hoc analysis and that it should be interpreted with caution, the OPDP said the statements were "not sufficient to mitigate the overall misleading impression created by the inclusion of this presentation."
The OPDP requested that BMS respond within 15 business days to the untitled letter to address the concerns, list all promotional communications for Krazati that contain similar misleading representations, and explain its plan to discontinue these misleading promotional communications or to cease distribution of Krazati.