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 ( T 1 mutant vs 2 mutants), 0. 8; ( 5 CI, 0.4 , 0. 4); 0.01 2 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. 4 (1.0 1.7 ) 0.027 1.2 (0. 1. 1) 0.14 0 Department of Genitourinary Oncology, Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, Platelets (109/L) 1. 4 (1.2 2.08) 0.001 1.55 (1.21 1. ) 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. 1.1 ) 0.402 1.12 (0.85 1.47) 0.40 40 Trust, London, UK; 7Pfizer Global Medical, Athens, Greece;8 Pfizer, Milan, Italy;9 Pfizer, San Diego, CA, USA;10 Memorial 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. 2 1.0 ) 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. 2 (1.02 1.70) 0.0 1.2 (0. 1 1.75) 0.1 0 Neutrophils (10 9/L) 20 1.41 (1.11 1.7 ) 0.004 1.54 (1.15 2.05) 0.00 *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. 5) 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 1.5 (1.25 2.01) 0.001 1.51 (1.1 1. ) 0.002 0 5 10 15 20 25 0 5 1.50 (1.14 1. 7) 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 1.0 (0.85 1. ) 0.501 0. (0.74 1.2 ) 0.78 No. at ris A Ax; T 1 mutant 2 0 200 1 87 10 0 • Baseline and on-treatment levels of ICAM-1, VEGF, CRP, and 0 1 2 0 1 2 A Ax; 2 mutants 7 7 55 42 17 1 0 Sunitinib; T 1 mutant 11 20 117 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 5 15 5 1 0 A Ax; T 1 mutant (n 2 0; events 170; median 11.1 months, 5 CI, .5 1 . ) the treatment arms (Figure 5) A + Ax (n = 434) S (n = 439) A + Ax (n = 402) S (n = 383) A Ax; 2 mutants (n 7 ; events 27; median 25.0 months, 5 CI, 20.7 NE ) SCOPE Sunitinib; T 1 mutant (n 11; events 1 8; median .2 months, 5 CI, 8.2 11.0 ) Sunitinib; 2 mutants (n ; events 50; median . months, 5 CI, 4.2 8.5 ) 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 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) A Ax (good vs intermediate), 0.8 ; ( 5 CI, 0. 04 1.215); 0.001 0 A Ax (good vs bad), 0.47; ( 5 CI, 0. 08 0.71 ); 0.001 2 0.5 Productively A Ax (intermediate vs bad), 0.55; ( 5 CI, 0. 40 0.88 ); 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 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 S Baseline C1/D15 C1/D2 C2/D1 C2/D15 C2/D2 C /D1 Baseline C1/D15 C1/D2 C2/D1 C2/D15 C2/D2 C /D1 Sunitinib HR (intermediate vs bad), 0.58; (95% CI, 0.380–0.890); p≤.0001 0 5 T-cell fraction immune fitness and treatment-specific immunomodulation 0.
ilit y o f 50 4 b Total T-cell IL-7 51.0 (51.0-51.0) 51.0 (51.0-51.0) 0.0034 40 0.4 ‡ 27.310 (25.832-28.790) 36.069 (34.860-38.031) <0.0001 ob a 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 0 5 0.0 0 MIP-1β 278.0 (268.0-302.0) 333.5 (307.0-368.0) 0.0035 Baseline C1/D15 C1/D2 C2/D1 C2/D15 C2/D2 C /D1 Baseline C1/D15 C1/D2 C2/D1 C2/D15 C2/D2 C /D1 Log2FC PFS, months A + Ax A + Ax multiple T-cell–related metrics No. at ris productively S S 0.092 (0.044-0.133) 0.449 (0.369-0.504) <0.0001 A Ax; good 1 8 157 117 80 4 1 0 VEGF 299.0 (281.0-317.0) 323.5 (284.0-357.0) 0.0755 A Ax; bad 44 24 1 1 0 rearranged A Ax; intermediate 84 5 44 2 7 4 0 Error bars indicate the SEM. § Sunitinib; good 22 1 5 10 58 18 0 T-cell fraction • A novel proteomic classifier was prognostic for PFS in both treatment arms Sunitinib; bad 44 18 5 2 0 IL, interleukin; MCP-1, monocyte chemotactic protein 1; MIP-1β, macrophage Sunitinib; intermediate 7 4 27 15 5 2 0 Log2FC in total T 0.046 (0.022-0.073) 0.364 (0.300-0.440) <0.0001 A Ax; good outcome (n 1 8, events 108, median 15.5 months 5 CI, 12.5-20.8 ) clone counts‡,§ inflammatory protein 1β;NLR , neutrophil-lymphocyte ratio; WT, wildtype. No differences A Ax; bad outcome (n 44, events 28, median . months 5 CI, 4.2- .0 ) Figure 5. Forest plots of PFS by most significant cytokine and A Ax; intermediate outcome (n 84, events 45, median 1 .2 months 5 CI, 11.1-17. ) Log2FC, log2 fold change; TCRseq, T-cell receptor sequencing. between arms were observed for any analyte either in WT or double-mutants. • A subset of “double-mutant” patients harboring ≥2 interchangeable Sunitinib; good outcome (n 22 , events 142, median 11.0 months 5 CI, .0-12.4 ) angiokine levels at baseline and C2D1, by treatment arm Sunitinib; bad outcome (n 44, events , median 4.4 months 5 CI, 2.7- .8 ) Sunitinib; intermediate outcome (n 7, events , median . months 5 CI, 4.2-8. ) *N varied depending on availability of baseline-C2D1 matched pairs. For Log2FC *For cell population n=601 for WT + single mutants and n=139 for double mutants. Baseline C2D1 productively rearranged T-cell fraction A + Ax (n=326) and S (n=310), and for Log2FC T mutations in a set of 10 genes detected in baseline tissue displayed For cytokine/angiokine n=513 for WT + single mutants and n=132 for for double mutants. HR, hazard ratio; MALDI-TOF, matrix-assisted laser desorption ionization–time of flight. HR (95% CI) HR (95% CI) clones A + Ax (n=326) and S (n=308); †Wilcoxon rank-sum test (2 sided); ‡Normalized to > global median vs ≤ global median > global median vs ≤ global median a unique baseline phenotype and a differential cytokine/angiokine MALDI-TOF proteomic signature was developed in second-line non-small cell lung cancer input DNA; §C2D1 vs baseline. †Wilcoxon rank-sum test (2 sided). population treated with avelumab monotherapy. 2-sided p-value is from log-rank test. HR (95% CI) p HR (95% CI) p Table 3. Greatest differences in circulating cytokine/angiokine levels at C2D1, by mutant subgroup and treatment arm response to treatment with A + Ax vs S 1. (1.02, 1.8 ) 0.0 7 0. (0.70, 1. 1) 0.777 Interleukin 10 2.25 (1. , .00) 0.001 1.52 (1.1 , 2.05) 0.005 Figure 2. Forest plots of PFS by TCRseq metrics at baseline and A + Ax S 0.77 (0.58, 1.00) 0.05 1.01 (0.75, 1. 7) 0. 52 C2D1, by treatment arm Interleukin 12β • Taken together, these data demonstrate the potential utility of novel 0.8 (0. 4, 1.0 ) 0.1 8 0.8 (0. 1, 1.12) 0.21 Cytokine/angiokine WT + single mutants Double mutants WT + single mutants Baseline C2D1 0.78 (0. 0, 1.02) 0.0 0.88 (0. 5, 1.18) 0. p* Double mutants (n=46) p* Interleukin 23 median (95% CI) (n=209) (n=66) (n=201) peripheral biomarkers as predictive or prognostic tools for response to HR (95% CI) HR (95% CI) 0. 0 (0.70, 1.1 ) 0.42 1.04 (0.78, 1. ) 0.781 ≥ global median vs ≥ global median vs 1.45 (1.0 , 1. 8) 0.01 1. 7 (1.18, 2. ) 0.004 HR (95% CI) p < global median < global median HR (95% CI) p Interleukin 6 BDNF 13.0 (12.0-15.0) 13.0 (11.0-14.0) 0.275 9.0 (7.9-9.7) 11.0 (8.4-13.0) 0.0259 A + Ax vs S 2. 1 (1.72, .12) 0.001 1.77 (1.25, 2.4 ) 0.001 0.8 (0. 1.14) 0.2 4 0.8 (0. 5 1.21) 0.45 1. 1 (1.00, 1.71) 0.051 1.44 (1.07, 1. ) 0.015 Productively rearranged Interleukin 8 T cells (fraction) 1.42 (1.10, 1.8 ) 0.00 1.22 (0. 2, 1. ) 0.1 7 Eotaxin-1 214.0 (189.0-235.0) 173.0 (148.0-204.0) 0.0143 179.0 (164.0-193.0) 174.0 (142.0-210.0) 0.7269 0.7 (0.57 0. 4) 0.014 0.5 (0.45 0.7 ) 0.001 1.14 (0.87, 1.4 ) 0. 4 1.21 (0. 1, 1. ) 0.1 5 ICAM-1 0.82 (0. 2 1.08) 0.155 0.8 (0. 1.21) 0.4 0 1.40 (1.0 , 1.80) 0.00 1.52 (1.14, 2.02) 0.004 Total T cells normalized MCP-1 435.0 (393.0-474.0) 380.0 (316.0-420.0) 0.0545 458.0 (423.0-489.0) 432.0 (343.0-490.0) 0.1641 to input DNA 0. (0.71, 1.22) 0.5 7 1.11 (0.82, 1.51) 0.4 0. 7 (0.52 0.8 ) 0.002 0.58 (0.4 0.7 ) 0.001 VEGF 1.48 (1.15, 1. 1) 0.002 1.4 (1.0 , 1. 5) 0.010 0.8 (0. 1.1 ) 0.425 0. 5 (0.70 1.28) 0.7 0 1. 2 (1.02, 1.72) 0.0 5 1. 7 (1.04, 1.81) 0.024 GET POSTER PDF Total T clones normalized CRP MIP-1β 312.0 (271.0-359.0) 404.0 (364.0-466.0) 0.0332 218.0 (194.0-240.0) 289.5 (233.0-354.0) 0.0008 GET PLAIN LANGUAGE SUMMARY to input DNA 1.71 (1. 4, 2.17) 0.001 1.40 (1.08, 1.82) 0. 011 Copies of this poster obtained through this hyperlink or quick response 0.7 (0.57 0. ) 0.045 0.57 (0.4 0.75) 0.001 0 1 2 4 0 1 2 4 (QR) code are for personal use only and may not be reproduced Please scan this quick response (QR) code with your smartphone Favors ≥ global median Favors global median Favors ≥ global median Favors global median MMP3 8.5 (8.1-9.4) 10.0 (8.9-12.0) 0.0536 9.9 (8.9-11.0) 11.0 (7.8-13.0) 0.6958 without permission from ASCO and the author of this poster app or click here to view a plain language summary of the 0 1 2 0 1 2 Favors ≥ global median Favors < global median Favors ≥ global median Favors < global median accepted scientific abstract Correspondence: Toni K. Choueiri, [email protected] A + Ax (n = 375) S (n = 364) A + Ax (n = 382) S (n = 3 5) A + Ax (n = 325) S (n = 289) VEGF 362.0 (341.0-401.0) 385.5 (332.0-432.0) 0.7129 244.0 (219.0-263.0) 303.0 (248.0-377.0) 0.0131 HR, hazard ratio; TCRseq, T-cell receptor sequencing. CRP, C-reactive protein; HR, hazard ratio; ICAM-1, intercellular adhesion molecule 1. HR (95% CI) from Cox proportional hazards model. Biomarker is dichotomized at global Cox proportional hazards model with ≤ global median as the reference group was used to BDNF, brain-derived neurotrophic factor; MCP-1, monocyte chemotactic protein 1; MIP-1β, macrophage inflammatory protein 1β;MMP3 , matrix metalloproteinase 3; VEGF, vascular median with < global median as the reference group. An HR of <1 indicates better PFS for calculate the HR and 95% CI. An HR of <1 indicates better survival in the > global median endothelial growth factor; WT, wild type. biomarker high (≥ global median) group. 2-sided p-value is from log-rank test. group. 2-sided p-value is from log-rank test. * Wilcoxon rank-sum test (2 sided).
REFERENCES 1. Bavencio (avelumab). Prescribing information. EMD Serono; 2020. 2. Inlyta (axitinib). Prescribing information. Pfizer; 2020.3. Motzer RJ, et al. N Engl J Med. 2019;380(12):1103-15. 4. Choueiri TK, et al. Ann Oncol. 2020;31(8):1030-9. 5. Motzer RJ, et al. Nat Med. 2020;26(11):1733-174. DISCLOSURES T. K. Choueiri: Owns stock and has received additional ownership interests from Pionyr and Tempest Therapeutics; has received honoraria from Alexion, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, GSK, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath, MSD, Michael J. Hennessy Associates, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Sanofi/Aventis, The New England Journal of Medicine, and UpToDate; has served in a consulting or advisory role for Alexion, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, GSK, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath, MSD, Michael J. Hennessy Associates, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, The New England Journal of Medicine, and UpToDate; has received institutional research funding from Agensys, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, Congressionally Directed Medical Research Programs (DOD), Corvus, Eisai, Exelixis, Foundation Medicine, Gateway for Cancer Research, GSK, Ipsen, MSD, NCI, Novartis, Peloton Therapeutics, Pfizer, Prometheus, Roche, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and TRACON Pharma; owns patents, royalties, and other intellectual property for international patent application PCT/US2018/058430, entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy” and international patent application PCT/US2018/12209, entitled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response”; and has received travel, accommodations, and expenses from Alexion, Alligent, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, GSK, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath, MSD, Michael J. Hennessy Associates, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, and The New England Journal of Medicine.A. C. Donahue: Employment by PfizerB. I. Rini: Stock and other ownership in PTC Therapeutics; has provided a consulting or advisory role for Bristol Meyers Squibb, Pfizer, Genentech/Roche, Aveo, Synthorx, Compugen, Merck & Co., Corvus, Surface Oncology, 3DMedicines Arravive, Alkermes, Arrowhead, GSK, and Shionogi; has received research funding from Pfizer, Merck & Co., Genentech/Roche, Aveo, AstraZeneca, Bristol Meyers Squibb, and Exelixis; and has received travel, accommodations, and expenses from Merck & Co., Pfizer, and Bristol Meyers Squibb.T. Powles: Has received honoraria from AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, EMD Serono, Astellas, Johnson & Johnson, Eisai, and Roche; has served in a consulting or advisory role at AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, EMD Serono, Astellas, Johnson & Johnson, Eisai, and Roche; has received research funding from AstraZeneca, Bristol Myers Squibb, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, EMD Serono, Astellas, Johnson & Johnson, Eisai, and Roche; and has received travel, accommodations, and expenses from Roche, Pfizer, MSD, AstraZeneca, and Ipsen.J. Haanen: Has served in a consulting or advisory role for the institution from Achilles Therapeutics, AIMM Therapeutics, Bristol Myers Squibb, Immunocore, Ipsen, MSD Oncology, Neogene Therapeutics, Neon Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, and Third Rock Ventures and has received institutional research funding from Amgen, Bristol-Myers Squibb, MSD, Neon Therapeutics, and Novartis. J. Larkin: Has received personal fees from Eisai, GSK, Kymab, Roche/Genentech, Secarna, Pierre Fabre, and EUSA Pharma and has received grants and personal fees from MSD, Pfizer, and Novartis.X.J. Mu: Employment by Pfizer; owns stock and other ownership in Pfizer; and has received research funding from Pfizer.J. Pu: Employment by Pfizer.D. Thomaidou: Employment by Pfizer.A. di Pietro: Employment by Pfizer and owns stock and other ownership in Pfizer.P. B. Robbins: Was an employee of Pfizer at the time the analysis was conducted.R. J. Motzer: Has served in a consulting or advisory role for Novartis, Eisai, Exelixis, Merck & Co., Genentech/Roche, Incyte, Lilly, Pfizer, AstraZeneca, EMD Serono, Calithera Biosciences; has received travel, accommodations, and expenses from Bristol Myers Squibb; and has received institutional research funding from Pfizer, Bristol Myers Squibb, Eisai, Novartis, Genentech/Roche. Exelixis, and Merck & Co.ACKNOWLEDGMENTS The authors would like to thank Shibing Deng for biostatistical analyses. The authors would also like to thank the patients and their families, investigators, co-investigators, and study teams at each of the participating centers and at Pfizer. This trial was sponsored by Pfizer and is part of an alliance between Pfizer and Merck KGaA, Darmstadt, Germany. Medical writing support was provided by Hiba Al-Ashtal of ClinicalThinking and was funded by Pfizer and Merck KGaA. Poster/Abstract No. 4547. Presented at the 2021 ASCO Annual Meeting, June 4-8, 2021; Virtual.