Immune-related adverse events (IRAE) pose a significant diagnostic and therapeutic challenge in patients treated with immuno-oncology (IO) drugs. IRAEs have been found to correlate with better outcome, but studies are conflicting on the magnitude and significance of this correlation. Estimating the true incidence of IRAEs is particularly difficult in the early phase 1/2 trial setting, with factors contributing to both over- and under-estimation. A key issue is the lack of IRAE diagnostic criteria, necessary to discriminate “pure” IRAEs from other treatment-related adverse events not sustained by an autoimmune process. We present the definitive analysis of a retrospective study conducted on patients treated with IO drugs within phase 1-2 trials at our institute.
We extensively reviewed clinical characteristics and temporal dynamics of IRAEs and empirically developed an IRAE Likelihood Score (ILS) based on availability of invasive or highly specific tests, response to immune suppression, temporal correlation with IO drug initiation, evidence ruling out alternative cause, known relationship with IO. We defined High Confidence (HC) or Low Confidence (LC) IRAEs by clinical consensus and estimated correlation with survival of treatment-related events by multivariate Cox analysis. To mitigate immortal time-bias, we also analysed data at 2-month landmark and modeling IRAEs as time-dependent covariate.
29.2% of 202 patients developed ≥ 1 treatment-related adverse event. ILS ≥ 5 discriminated between HC and LC IRAEs with >93% specificity and sensitivity. HC IRAE patients (n=24) had significantly improved outcome for PFS and OS, irrespective of the model used (landmark, time-dependent or uncorrected, HR for PFS ranging 0.24-0.44, for OS 0.18-0.23, all p values <0.01), whereas LC IRAE patients (n=35) showed no statistically significant correlation.
ILS provides a simple system to identify bona fide IRAEs, pruning for other treatment-related events likely due to different pathophysiology. Applying stringent criteria leads to lower and more reliable estimates of IRAE incidence and identifies events with significant impact on survival.
The authors.
Italian Ministry of Health.
L. Mazzarella: Financial Interests, Personal, Advisory Board, Member of Scientific Advisory Board: Tethis. C. Criscitiello: Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Eli-Lilly, Roche; Financial Interests, Personal, Advisory Board: MSD, Seagen. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Ellipsis, Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences; Financial Interests, Personal, Advisory Board, Advisory Board: Exact Science, Celcuity; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Personal, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Personal, Advisory Role, Member of the Scientific Council. Patient Advocacy Association: Europa Donna; Non-Financial Interests, Personal, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Personal, Invited Speaker, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Personal, Officer, Member of the Advisory Council: EUSOMA. All other authors have declared no conflicts of interest.