Integrating Peripheral Biomarker Analyses From
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BACKGROUND METHODS • The combination of avelumab, an anti–PD-L1 monoclonal • Previous work demonstrated that outcomes of patients • Biomarkers in baseline and on-treatment blood samples from • Circulating proteins were analyzed via multiplex Luminex Integrating peripheral biomarker analyses from JAVELIN antibody, and axitinib, a vascular endothelial growth factor with interchangeable multiple mutations (termed “double 886 enrolled patients were correlated with clinical outcomes cytokine analyses and proteomic matrix-assisted laser desorption receptor (VEGFR) tyrosine kinase inhibitor, is approved as a mutants”) in a set of 10 identified genes were associated with and molecular profiling data from corresponding tumor ionization–time of flight (MALDI-TOF) mass spectrometry first-line treatment for patients with aRCC1,2 prolonged PFS in the A + Ax arm5 samples; the previously published definition of baseline tumor • PFS analyses were conducted with and without age and sex Renal 101: avelumab + axitinib (A + Ax) vs sunitinib (S) tissue “double-mutant” patients5 was further refined • In the phase 3 JAVELIN Renal 101 trial (NCT02684006), • We report the association of blood-based biomarkers with adjustment with no observable differences; nonadjusted data treatment-naive patients with aRCC receiving A + Ax showed differential responses to treatment with either A + Ax or S, and • Levels of mature T cells were examined by T-cell receptor are presented. in advanced renal cell carcinoma (aRCC) improved PFS and objective response rate compared with with specific genomic variants in tumor tissue sequencing (TCRseq), and peripheral blood cell populations patients receiving S3,4 were assessed via complete blood count with differential RESULTS • A novel proprietary proteomic signature was shown to be Figure 3. Forest plots of PFS by peripheral cell populations at Figure 6. Kaplan-Meier plot of PFS by treatment arm and mutant Table 2. Differences in peripheral blood cell populations and selected prognostic for both both A + Ax and S (Figure 1) 1 2 3 4 5 6 2 baseline and C2D1, by treatment arm subgroup cytokines/angiokines at baseline, by mutant subgroup T. K. Choueiri, A. C. Donahue, B. I. Rini, T. Powles, J. Haanen, J. Larkin, X. J. Mu, nstratified • In the S arm only, both baseline and on-treatment T-cell levels Baseline C2D1 100 A+Ax HR (WT+1 mutant vs 2+ mutants), 2.42; (95% CI, 1.601, 3.669); p≤.0001 2 7 8 9 10 Sunitinib (T1 mutant vs 2 mutants), 0.8; (5 CI, 0.4, 0.4); 0.012 J. Pu, D. Thomaidou, A. di Pietro, P. B. Robbins, * R. J. Motzer were associated with PFS benefit Figure( 2); T cells showed HR (95% CI) HR (95% CI) 0 ≥ global median vs ≥ global median vs 9 WT + single mutants Double mutants † 80 Cell population, ×10 /L p HR (95% CI) p global median global median HR (95% CI) p 1 2 3 much greater expansion at cycle 2 day 1 (C2D1) following S median (95% CI)* median (95% CI)* Dana-Farber Cancer Institute, Boston, MA, USA; Pfizer, La Jolla, CA, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 70 treatment (Table 1) 4 1.34 (1.03 –1.73) 0.027 1.23 (0.93 –1.61) 0.143 0 Department of Genitourinary Oncology, Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, Platelets (109/L) 1.64 (1.29–2.08) <0.001 1.55 (1.21–1.99) <0.001 Leukocytes 7.100 (6.900-7.300) 6.270 (6.000-6.700) <0.0001 St Bartholomew’s Hospital, London, UK; 5Netherlands Cancer Institute, Amsterdam, the Netherlands; 6Royal Marsden NHS Foundation • Peripheral blood cell subset levels were differentially associated 50 0.0 (0.69–1.16) 0.402 1.12 (0.85 –1.47) 0.406 40 Trust, London, UK; 7Pfizer Global Medical, Athens, Greece; 8Pfizer, Milan, Italy; 9Pfizer, San Diego, CA, USA; 10Memorial Sloan Kettering Lymphocytes (109/L) with PFS at baseline and C2D1, both within and between Probability of PFS 0.70 (0.55–0.88) 0.002 0.80 (0.62–1.03) 0.078 0 Basophils 0.040 (0.030-0.040) 0.030 (0.020-0.040) 0.3168 Cancer Center, New York, NY, USA treatment arms (Figure 3) 1.32 (1.02–1.70) 0.033 1.26 (0.91–1.75) 0.10 Neutrophils (10 9/L) 20 1.41 (1.11–1.79) 0.004 1.54 (1.15 –2.05) 0.003 *Affiliation at the time the study was conducted. 10 • Treatment-emergent effects on peripheral cell counts were 1.08 (0.84 –1.40) 0.545 1.25 (0.4 –1.65) 0.122 Eosinophils 0.160 (0.140-0.190) 0.150 (0.110-0.200) 0.9477 NLR 0 more moderate with A + Ax vs S, and changes in these 1.59 (1.25 –2.01) <0.001 1.51 (1.16–1.96) 0.002 0 5 10 15 20 25 0 5 1.50 (1.14 –1.97) 0.004 1.10 (0.82–1.48) 0.517 PFS, months populations mirrored S dosing schedule (Figure 4) Monocytes (109/L) Lymphocytes 1.580 (1.500-1.610) 1.520 (1.410-1.630) 0.3224 1.09 (0.85 –1.39) 0.501 0.96 (0.74–1.26) 0.783 No. at ris AAx; T1 mutant 20 200 1 87 39 10 0 • Baseline and on-treatment levels of ICAM-1, VEGF, CRP, and 0 1 2 3 0 1 2 3 AAx; 2 mutants 7 7 55 42 17 6 1 0 Sunitinib; T1 mutant 11 20 117 63 1 4 0 Monocytes 0.600 (0.560-0.600) 0.500 (0.440-0.540) 0.0019 several interleukins showed differential associations with PFS in Favors ≥ global median Favors global median Favors ≥global median Favors global median Sunitinib; 2 mutants 63 5 15 9 5 1 0 AAx; T1 mutant (n 20; events 170; median 11.1 months, 5 CI, .51.) the treatment arms (Figure 5) A + Ax (n = 434) S (n = 439) A + Ax (n = 402) S (n = 383) AAx; 2 mutants (n 7; events 27; median 25.0 months, 5 CI, 20.7NE) SCOPE Sunitinib; T1 mutant (n 11; events 18; median .2 months, 5 CI, 8.211.0) Sunitinib; 2 mutants (n ; events 50; median . months, 5 CI, 4.28.5) Neutrophils 4.480 (4.320-4.600) 4.100 (3.740-4.400) 0.0013 • Double-mutant patients treated with A + Ax had prolonged NLR, neutrophil-lymphocyte ratio. • HR (95% CI) from Cox proportional hazards model. Biomarker is dichotomized at global 2+, double mutant; HR, hazard ratio; NE, not estimable; WT, wildtype. This analysis reports the correlation of clinical outcomes with baseline PFS, while those treated with S fared worse (Figure 6) median with < global median as reference group. An HR of <1 indicates better PFS for Double-mutant patients are classified as having ≥2 variants in baseline tumor tissue: Platelets 259 (250-266) 250 (230-278) 0.6339 and on-treatment blood-based biomarkers in patients with aRCC treated • Double-mutant status in baseline tumor was associated with biomarker high (≥ global median) group. 2-sided p-value is from log-rank test. somatic variants in any of 6 specific genes CD163L1( , DNMT1, MC1R, ABCA1, MYH7B, and STAB2) and/or germline single-nucleotide polymorphisms in any of 4 specific genes NLR 2.846 (2.676-3.000) 2.830 (2.478-3.129) 0.2379 with A + Ax or S differences in baseline blood cell subsets, as well as baseline (LOC728763, FOXO1, SPATA31C2, IL16 [P9L]). HR reference level is 2+ mutants, 2-sided and on-treatment angiokine/cytokine levels (Tables 2 and 3) Figure 4. Line plot of peripheral cell population counts over time, p-value is from log-rank test. by treatment arm Cytokine/angiokine 8 2.0 Figure 1. Kaplan-Meier plot of PFS by treatment arm and Table 1. TCRseq metrics at C2D1 by treatment arm Eotaxin 1 170.0 (153.0-182.0) 142.5 (118.0-157.0) 0.0095 6 1.5 proteomic classifier A + Ax (n=328)* S (n=311)* † CONCLUSIONS 4 1.0 TCR metric p nstratified Factor VII 451.0 (436.0-468.0) 471.5 (453.0-494.0) 0.1131 100 median (95% CI) median (95% CI) AAx (good vs intermediate), 0.8; (5 CI, 0.041.215); 0.001 0 AAx (good vs bad), 0.47; (5 CI, 0.080.71); 0.001 2 0.5 Productively AAx (intermediate vs bad), 0.55; (5 CI, 0.400.88); 0.001 Leukocytes (109/L) Lymphocytes (109/L) • Response to treatment with first-line A + Ax or S was associated with 80 Sunitinib HR (good vs intermediate), 0.66; (95% CI, 0.494–0.890); p≤.0001 IL-17 2.6 (2.6-2.6) 2.6 (2.6-2.6) 0.0674 S 0 0.0 rearranged 0.199 (0.188-0.211) 0.261 (0.250-0.271) <0.0001 70 Sunitinib HR (good vs bad), 0.39; (95% CI, 0.262–0.568); p≤.0001 PF Baseline C1/D15 C1/D29 C2/D1 C2/D15 C2/D29 C/D1 Baseline C1/D15 C1/D29 C2/D1 C2/D15 C2/D29 C/D1 f Sunitinib HR (intermediate vs bad), 0.58; (95% CI, 0.380–0.890); p≤.0001 5 0 0.6 T-cell fraction immune fitness and treatment-specific immunomodulation y o ilit 50 4 b Total T-cell IL-7 51.0 (51.0-51.0) 51.0 (51.0-51.0) 0.0034 a 40 0.4 ‡ 27.310 (25.832-28.790) 36.069 (34.860-38.031) <0.0001 ob 3 r counts P 0 • Multiple biomarkers were differentially associated with progression-free 20 2 MCP-1 394.0 (372.0-421.0) 331.5 (306.0-386.0) 0.0060 0.2 Total T clone 10 0.792 (0.708-0.851) 1.035 (0.955-1.073) <0.0001 1 ‡ 9 9 counts survival (PFS) in A + Ax vs S, including monocyte counts and levels of 0 Monocytes (10 /L) Neutrophils (10 /L) 0 5 10 15 20 25 30 35 0.0 0 MIP-1β 278.0 (268.0-302.0) 333.5 (307.0-368.0) 0.0035 Baseline C1/D15 C1/D29 C2/D1 C2/D15 C2/D29 C/D1 Baseline C1/D15 C1/D29 C2/D1 C2/D15 C2/D29 C/D1 Log2FC PFS, months A + Ax A + Ax multiple T-cell–related metrics No.