Novel PET RANO BM 1.0 criteria: Regulatory perspectives on new endpoint definitions in brain metastases

The aim of many emerging classifications for antitumor response is to develop predictive “surrogate” endpoints that closely reflect the effect of treatments on relevant clinical benefit measures, such as duration of overall survival, and can be assessed earlier in the course of the disease. When surrogacy is effectively demonstrated, these surrogates can serve as substitutes for clinical endpoints for various purposes, significantly enhancing drug development efficiency and clinical practice.

Albert and colleagues introduced the new PET Response Assessment in Neuro-Oncology (RANO) BM 1.0 criteria to allow metabolic response assessment of brain metastases using amino acid PET.¹ These standardized criteria complement the MRI-based RANO 1.0 criteria for brain metastases, using the same key parameters.² Progressive disease (PET-PD) is defined as ≥30% increase in maximum target-to-background ratio (TBR_max); or ≥10% in TBR_mean; or ≥40% in PET volume of any target lesion; or the appearance of any new measurable lesion. Partial response (PET-PR) is defined as all target lesions showing corresponding decrease in TBRs or PET volume; or a change from “measurable” to “nonmeasurable” disease; and no other response definition fulfilled. The new criteria aim to facilitate the incorporation of molecular imaging into clinical trials investigating novel treatment approaches, to provide more relevant and specific information for clinical decision-making.

A key question arises: Is this novel metabolic response endpoint suitable for regulatory purposes? While, admittedly, these new criteria require further validation and refinement through dedicated studies—an endeavor that warrants encouragement—the complexities involved in demonstrating surrogacy in rapidly evolving fields have to be acknowledged. Prospective “validation” needs to happen on 2 levels: The comparison between the newly introduced PET criteria compared to the CT/MRI-based criteria and the surrogacy of the newly introduced response criteria with relevant clinical endpoints.

Concerning the latter, even if surrogacy is not established, antitumour response endpoints might play a key role in early cancer drug development. Response endpoints tend to be less susceptible to external influences in measuring treatment effects, which is an advantage over other endpoints in nonrandomized trials. Importantly, response can be observed earlier and is therefore particularly suitable for “exploratory” or “hypothesis-generating” nonrandomized clinical trials aiming to readily inform sponsors about subsequent clinical drug development.

In addition to enhancement of drug development, the newly proposed metabolic response endpoint (complementing the traditional CT/MRI response) might play a pivotal role in regulatory submissions, to inform expedited approval processes—such as “conditional approval” in the EU, “accelerated approval” in the United States, and “temporary authorization” in Switzerland—based on nonrandomized studies involving patients with high unmet medical needs. In expedited approval submissions, magnitude and duration of the antitumor effect, in specific sites and overall, may be considered together with other factors, like the toxicity profile’s acceptability, the timeliness of confirmatory studies, corroborative mechanistic data, existing treatment options, unmet medical needs, and clarity regarding uncertainties. This necessitates transparent communication regarding the expert opinions behind response endpoints, emphasizing that they do not substitute for clinical evidence of benefit, and that clinical effect remains uncertain. Any claims of benefits of antitumor response in specific sites, separately from overall response, also require careful communication.

Another possible purpose for response endpoints is as corroborating evidence to inform regulatory submissions based on other endpoints like overall survival or progression-free survival, when these effects are less clear. Of note, the definition of “progression” within response assessment is also crucial for adjudicating the progression-free survival endpoint systematically reported in trials as part of regulatory submissions.

When surrogacy is not established, the most practical method for substantiating the relevance of response endpoints is to achieve broad scientific consensus based on analyses and endorsements from experts. The RANO group has employed a consensus process to define the new response assessment criteria for brain metastases aiming to improve accuracy, objectivity, and reliability. This is the starting point in order to gain credibility and can be further supported by wide acceptance within the scientific and patient community, following open discussions. Identifying, highlighting, and addressing any weaknesses or criticisms is essential. This can be achieved through systematic studies that gather insights about the new criteria along with their perceived clinical benefits and uncertainties.

In conclusion, the PET RANO criteria proposed by Albert and colleagues represent a significant evolution, introducing patient management and treatment evaluation modalities using advanced imaging techniques, based on an authoritative new standard framework. These criteria have the potential to further support the development of therapeutic innovations for patients with high unmet medical needs and to impact clinical decisions. The impact of these new criteria in informing regulatory decisions will be further enhanced with the accumulation of validating data and documentation of broad acceptance within the scientific and patient communities.

Disclaimer

The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties, or Swissmedic. This text is the sole product of the author(s) and that no third party had input or gave support to its writing.

References