<div>AbstractPurpose:<p>Adjuvant immunotherapy produces durable benefit for patients with resected melanoma, but many develop recurrence and/or immune-related adverse events (irAE). We investigated whether baseline serum autoantibody (autoAb) signatures predicted recurrence and severe toxicity in patients treated with adjuvant nivolumab, ipilimumab, or ipilimumab plus nivolumab.</p>Experimental Design:<p>This study included 950 patients: 565 from CheckMate 238 (408 ipilimumab versus 157 nivolumab) and 385 from CheckMate 915 (190 nivolumab versus 195 ipilimumab plus nivolumab). Serum autoAbs were profiled using the HuProt Human Proteome Microarray v4.0 (CDI Laboratories, Mayaguez, PR). Analysis of baseline differentially expressed autoAbs was followed by recurrence and severe toxicity signature building for each regimen, testing of the signatures, and additional independent validation for nivolumab using patients from CheckMate 915.</p>Results:<p>In the nivolumab independent validation cohort, high recurrence score predicted significantly worse recurrence-free survival [RFS; adjusted HR (aHR), 3.60; 95% confidence interval (CI), 1.98–6.55], and outperformed a model composed of clinical variables including PD-L1 expression (<i>P</i> < 0.001). Severe toxicity score was a significant predictor of severe irAEs (aHR, 13.53; 95% CI, 2.59–86.65). In the ipilimumab test cohort, high recurrence score was associated with significantly worse RFS (aHR, 3.21; 95% CI, 1.38–7.45) and severe toxicity score significantly predicted severe irAEs (aHR, 11.04; 95% CI, 3.84–37.25). In the ipilimumab plus nivolumab test cohort, high autoAb recurrence score was associated with significantly worse RFS (aHR, 6.45; 95% CI, 1.48–28.02), and high severe toxicity score was significantly associated with severe irAEs (aHR, 23.44; 95% CI, 4.10–212.50).</p>Conclusions:<p>Baseline serum autoAb signatures predicted recurrence and severe toxicity in patients treated with adjuvant immunotherapy. Prospective testing of the signatures that include datasets with longer follow-up and rare but more severe toxicities will help determine their generalizability and potential clinical utility.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-22-1664" target="_blank">See related commentary by Hassel and Luke, p. 3914</a></i></p></div>
<p>Supplemental Figure 1: Appendix cancer specific survival in patients with stage IV appendiceal adenocarcinoma stratified by presence of a germline variant. Highlighted Kaplan Meier curve areas display the 95% confidence interval for the respective survival curves.</p>
<p>Peripheral blood mononuclear cells (PBMCs) were separated from whole blood by Ficoll-Paque layering. (A) Concentration : effect relationship was determined for ACY-1215 at 24 and 48 hours in PBMCs. No cytotoxicity was observed after 24 and 48 hours of exposure. The IC50 was not reached at 24 and 48 hours. (B) Treatment of PBMCs with ACY-1215 1500 nM led to no induction of the UPR as demonstrated by Western blot analysis. (C) Dual targeting of protein degradation pathways with ACY-1215 and bortezomib led to no cytotoxicity in PBMCs and the combination is not synergistic. Cells were treated with increasing concentrations of ACY-1215 (0, 500, 1000, and 1500nM) plus bortezomib 3 nM for 48 hours. Synergy was calculated using Excess over Bliss where values greater than 10 represent synergy.</p>
<p>Appendix cancer specific survival in patients with stage IV appendiceal adenocarcinoma stratified by presence of a germline variant in CHEK2 (n=3) or BRCA1(n=1) associated with homologous recombination deficiency (HRD). Patients with germline variants in non-HRD-associated genes were not included in the analysis. Highlighted Kaplan Meier curve areas display the 95% confidence interval for the respective survival curves.</p>
e22046 Background: Immune checkpoint inhibition (ICI) improves progression-free survival (PFS) and overall survival (OS) for patients with metastatic melanoma (MM), but treatment may cause serious immune-related adverse events (irAEs) that require the use of immunosuppressive steroids. Skin toxicity (ST), the most common side effect, has been reported to be associated with better response to ICI in some studies but not others. Herein, we tested the hypothesis that the portended survival benefit associated with ICI-related ST reaches a threshold in MM patients, dependent on the severity of the ST. Methods: We analyzed MM patients enrolled prospectively in a clinicopathological database with protocol-driven follow up and treated with ICI at NYULH. The patient and/or physician reported the ST, and an immunologist-dermatologist independently confirmed the event was ICI-related. Severe ST was defined as a skin event that required treatment with systemic steroids. Other site-specific toxicities were recorded using the CTCAE v5.0. We tested the associations between ST and PFS and OS, stratified by no, mild, and severe ST, adjusting for age, gender, number of metastatic sites, LDH, and ECOG score at treatment initiation. Results: The cohort included 256 MM patients (387 lines of ICI treatments). ST was the most common irAE (34%), and was significantly associated with development of endocrine toxicity (P = 0.007). Of the ST events (n = 130), 66% were mild and 34% were severe. Compared to none, mild ST was significantly associated with improved PFS (adjusted hazard ratio [aHR] = 0.58 [0.38, 0.89], P = 0.01), and a similar trend was observed with OS (aHR = 0.68 [0.45, 1.03], P = 0.06). However, the positive effect was reduced to insignificant (PFS P = 0.53; OS P = 0.25) in patients who developed severe ST irAEs that required systemic steroids. Conclusions: Our data demonstrate that ICI-induced ST is a complex phenomenon and might explain the discordance of reported data. While the worse outcome in patients with severe ST compared to mild may stem from steroidal immunosuppression, a threshold may also exist wherein severe ST itself might contribute to a relative reduction in ICI efficacy. More research is needed to elucidate the mechanisms that link ST and response to ICI in order to better characterize and treat skin irAEs without systemically suppressing anti-tumor immunity.
Supplementary Data from Baseline Serum Autoantibody Signatures Predict Recurrence and Toxicity in Melanoma Patients Receiving Adjuvant Immune Checkpoint Blockade
<p>Supplemental Table 1. Patient, slide, and tile distribution during the 5-fold cross validation for training the neural network on the NYU dataset. Supplemental Table 2. Odds Ratios (OR) and 95% Confidence Intervals (CI) from univariate analyses of baseline clinical and demographic variables. Supplemental Table 3. AUC for each of 5 independent test runs and the average AUC for both classifiers when applied to Vanderbilt slides scanned with the Aperio AT2. Supplemental Table 4. AUC for each of 5 independent test runs and the average AUC for both classifiers when applied to Vanderbilt slides scanned with the Leica SCN400. Supplemental Table 5. AUC with 95% confidence intervals for the DCNN and multivariable classifiers when applied exclusively to lymph node or soft tissue from the Vanderbilt dataset. Supplemental Table 6. Results of 3 independent test runs and the average performance of the DCNN classifier on slides from Vanderbilt scanned at 10x magnification. Shown are area under the curve (AUC) and 95% confidence intervals (CI). Supplemental Table 7. Hazard Ratios (HR) with 95% Confidence Intervals (CI) for the clinical variables used in the multivariable prediction model. Supplemental Table 8. AUC and 95% confidence intervals for the neural network prediction, ECOG performance status, treatment category, and each combination of the variables. Supplemental Table 9. Value importance of treatment category, baseline ECOG, and DCNN are reported as the absolute value of the Z-score. Supplemental Table 10. Confusion matrix for predictions of PFS on the cohort of Vanderbilt patients when slides were scanned with an Aperio AT2 scanner. Supplemental Table 11. Confusion matrix for predictions of PFS on the cohort of Vanderbilt patients when slides were scanned with a Leica SCN400 scanner.</p>
