Immune-Related Response Criteria Derived From RECIST v1.1 (irRECIST)

Given the evolving research and regulatory landscape with multiple versions of irRECIST implemented by different Sponsors and the position from Health Authorities regarding the role of irRECIST (purely exploratory), implementation of irRECIST in new protocols is not recommended.

Increasing clinical experience indicates that traditional response criteria may not be sufficient to fully characterize activity in this new era of targeted therapies and/or biologics.

This is particularly true for immunotherapeutic agents such as anti-CTLA4 and anti-PD-1PD-L1 which exert the antitumor activity by augmenting activation and proliferation of T-cells, thus leading to tumor infiltration by T-cells and tumor regression rather than direct cytotoxic effects (Hodi et al, 2008; Hoos et al, 2010).

Clinical observations of patients with advanced melanoma treated with ipilimumab, for example, suggested that conventional response assessment criteria such as RECIST and WHO criteria are not sufficient to fully characterize patterns of tumor response to immunotherapy because tumors treated with immunotherapeutic agents may show additional response patterns that are not described in these conventional criteria (Wolchok et al, 2009; Nishino et al, 2013).

Furthermore, the conventional tumor assessment criteria (RECIST and WHO) have been reported as not capturing the existence of a subset of patients who have an OS similar to those who have experienced CR or PR but were flagged as PD by WHO criteria (Wolchok et al, 2009; Nishino et al, 2013).

On these grounds, a tumor assessment system has been developed that incorporates these delayed or flare-type responses into the RECIST v1.1 criteria (irRECIST) (Nishino et al, 2012).

For irRECIST, with the exception of a complete response assessment, only target and new measurable lesions are taken into account.

In contrast to RECIST v1.1, the irRECIST:

• Requires confirmation of both progression and response by imaging at least 4 weeks from the date first documented, and

• Does not necessarily score the appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and measurable new lesions does not increase by \(≥\) 20%.

The same method of assessment and the same technique should be used to characterize each identified and reported target lesion(s) at baseline and throughout the study.

irRECIST responses are defined as follows:

• Overall immune-related complete response (irCR): Complete disappearance of all lesions (whether measurable or not) and no new lesions. All measurable lymph nodes also must have a reduction in short axis to \(<\) 10 mm.

• Overall immune-related partial response (irPR): Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases \(≥\) 30%.

• Overall immune-related stable disease (irSD): Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions does not meet criteria for irCR or irPR, (compared to baseline) or immune-related progressive disease (irPD, compared to nadir).

• Overall immune-related progressive disease (irPD): Sum of the diameters (longest for non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions increases ≥ 20% (compared to nadir), confirmed by a repeat, consecutive observation at least 4 weeks from the date first documented.

New measurable lesions: Incorporated into tumor burden (ie, added to the target lesion measurements). A lymph node has to be \(\ge\) 15 mm in short axis to be a measurable new lesion and its short axis measurement is included in the sum. Up to 2 new lesions per organ and up to 5 new lesions in total can be added to the measurements.

New non-measurable lesions: Do not define progression but preclude irCR.

Overall responses derived from changes in target, non-target, and new lesions are outlined in the following Table 1.

Table 1. Overall Responses Derived From Changes in Target, Non-Target, and New Lesions

[a] Decreases assessed relative to baseline

[b] Response (irCR and irPR) and progression (irPD) must be confirmed by a second, consecutive assessment at least 4 weeks apart. IrCR = immune-related complete response; irPR = immune-related partial response; irSD = immune-related stable disease; irPD = immune-related progressive disease.