Abstract
Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma1,2, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy2. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%2. Here we report on the first pilot combination neoadjuvant trial (NCT02812420) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease3,4,5. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment.
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Data availability
The data generated or analyzed during this study are included in this article along with its supplementary information files. All WES and gene expression NanoString data that support the findings of this study (Fig. 2a–c and Extended Data Figs. 4, 5 and 8) are deposited in the European Genome-phenome Archive under accession number EGAS00001004074. The links to databases used for analysis of the data presented in this study: COSMIC, EXAC, ESP600, 1000 Genomes and UCSC Genome Browser are listed in Supplementary Table 6. All other relevant data related to the current study are available from the corresponding author (P.S.) on reasonable request, which does not include confidential patient information.
Code availability
No custom codes were used in analyses reported in this study. All relevant references are provided in the Methods.
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Acknowledgements
This research is supported in part through an alliance between AstraZeneca/MedImmune and the MDACC Immunotherapy Platform, the MD Anderson Physician Scientist Award (J.G.), Khalifa Physician Scientist Award (J.G.), Andrew Sabin Family Foundation Fellows Award (J.G.) and Wendy and Leslie Irvin Barnhart Fund (J.G.). We thank the genomic medicine, CGL core team for WES. In addition, we thank Ashura Khan (Program Director) and the Immunotherapy Platform team for technical support. P.S. and J.P.A. are members of the Parker Institute for Cancer Immunotherapy, which supports their research work at MDACC.
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P.S. conceptualized clinical trial and design and supervision of immune monitoring studies. J.G. served as Principal Investigator of the clinical trial and supervised the clinical trial. R.S.T. and Y.S. performed statistical analysis. J.G., P.S., S.S.Y., S.G. and O.A. Contributed to writing, review and/or revision of the manuscript. N.M., C.D., A.S.-R., M.T.C., C.C.G, A.M.K., S.F.M., J.C.A., A.Y.S., P.M., P.C., J.W., J.N.P., J.M.B., F.D., S.B., W.L., Y.S., Y.Z., M.D.M., Y.W., J.C., J.Z., A.F. and J.P.A. provided administrative, technical or material support (reporting or organizing data and constructing databases).
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J.G. served as a consultant on a scientific advisory board for AstraZeneca and received compensation as an advisor. A.M.K. served on a scientific advisory board for AstraZeneca and received compensation as an advisor. A.S.-R. is on a scientific advisory board for AstraZeneca and receives compensation as an advisor. J.B. became an AstraZeneca employee after the work on this manuscript was completed. P.S. and J.P.A. do not have any competing interest with this manuscript. However, they provided a list of all disclosures for transparency. P.S. has ownership in Jounce, BioNTx, Constellation, Oncolytics, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Dragonfly, Lytix, Lava Therapeutics, Infinity Pharma, Adaptive Biotechnologies and Hummingbird. J.P.A. has ownership in Jounce, BioNTx, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Adaptive Biotechnologies and Codiak. P.S. serves as a consultant for Constellation, Jounce, Kite Pharma, Neon, BioAtla, Oncolytics Biotech, Forty-Seven, Polaris, Apricity, Marker Therapeutics, Codiak, ImaginAb, Dragonfly, Lava Therapeutics, Infinity Pharma, Lytix and Hummingbird. J.P.A. serves as a consultant for Jounce, Neon, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAb, Lava Therapeutics, Dragonfly, Lytix and Hummingbird. J.G. serves as a consultant for ARMO Biosciences, CRISPR Therapeutics, Jounce, Nektar, Pfizer, Polaris and Symphogen.
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Extended data
Extended Data Fig. 1 Trial schema (NCT02812420).
Patients each had baseline TURBT for tumor resection, pathologic diagnosis, staging, and risk stratification. The first cohort of 28 patients each received durvalumab at 1500 mg plus tremelimumab 75 mg every 4 weeks for a total of 2 doses. The second cohort of 17 patients was planned to receive durvalumab at 1500 mg plus tremelimumab 300 mg x 1 dose and then only durvalumab at 1500 mg 4 weeks later (not reported in this manuscript). Surgery (radical cystectomy or applicable surgery to resect tumors) was performed 4–6 weeks after the last dose of treatment. A cystoscopy (or applicable imaging) with optional TURBT was performed at week 4 (post-treatment dose 1) to rule out patients with rapid disease progression. In the case of rapid disease progression, these patients were taken off the trial per clinical judgement from the treating physicians and the principal investigators. Pre- and post-treatment blood and tumor tissues were collected for correlative studies. TURBT-transurethral resection of bladder tumor. * A cystoscopy and optional TURBT prior to second dose.
Extended Data Fig. 2 Response rate in association with adverse events or variant histology.
a, Pathologic response based on grade of immune-related adverse events. b, Pathologic response in pure urothelial carcinoma vs. urothelial carcinoma with variant histology.
Extended Data Fig. 3 Distribution of PD-L1 expression in the immune and tumor cell compartments in pre-treatment tumor tissues of responders compared to non-responders.
a, Box plot showing density of immune cells expressing PD-L1 in pre-treatment tumor tissue samples from responders (R, n = 13, red) and non-responders (NR, n = 13, blue). b, Box plot showing density of tumor cells expressing PD-L1 in pre-treatment tumor tissue samples from responders (R, n = 13, red) and non-responders (NR, n = 13, blue). In the box plots of a and b, the horizontal bold line represents the median. The lower and upper hinges of the box correspond to the first and third quartiles (the 25th and 75th percentiles); the upper whisker extends from the hinge to the largest value no further than 1.5 × IQR from the hinge (where IQR is the distance between the first and third quartiles); and the lower whisker extends from the hinge to the smallest value at most 1.5 × IQR from the hinge. Statistical analysis was performed using two-sided Wilcoxon rank-sum test. P < 0.05 is considered statistically significant.
Extended Data Fig. 4 Predicted neoantigen load in pre-treatment tumor tissue samples.
Box plot showing neoantigen load did not differ significantly between the R (n = 13, red) and NR (n = 10, blue) patients. The horizontal bold line represents the median. The lower and upper hinges of the box correspond to the first and third quartiles (the 25th and 75th percentiles); the upper whisker extends from the hinge to the largest value no further than 1.5 × IQR from the hinge (where IQR is the distance between the first and third quartiles); and the lower whisker extends from the hinge to the smallest value at most 1.5 × IQR from the hinge. The P value was calculated using two-sided Wilcoxon rank sum test. P < 0.05 is considered statistically significant.
Extended Data Fig. 5 Mutational analysis of specific genes in pre-treatment tumor tissue samples in correlation with response.
a, CoOncoplot showing mutations in DNA-damage response (DDR) genes in responders (R, n = 13, right) and non-responders (NR, n = 10, left). b, CoOncoplot showing mutations in KRAS, PIK3CA, PBRM1, EGFR, NRAS, APC2 and FGFR genes in responders (R, n = 13, right) and non-responders (NR, n = 10, left). Each row represents a gene and the gene name is listed in the middle of the two heatmaps and their respective frequencies are listed on the left of the first heatmap (NR) and on the right of the second heatmap (R). Each column represents a patient. Each row represents a gene and the gene name is listed in the middle of the two heatmaps and their respective frequencies are listed on the left of the first heatmap (NR) and on the right of the second heatmap (R). The p-values comparing the distribution of mutations between R and NR are shown within parentheses next to each gene name. N/A denotes not applicable. The colors of rectangles in the body of the heatmap indicates different types of somatic mutations and the key identifying each mutation type is shown at the bottom. P values calculated using two-sided Fisher’s exact test.
Extended Data Fig. 6 Biological responses in peripheral blood and tumor tissue samples after treatment with durvalumab plus tremelimumab.
a–e, Immune profiling by CyTOF analysis was performed on peripheral blood samples collected pre- and post-treatment. a-c, Categorical scatter plots showing frequency of subsets of CD4 T cells expressing PD-1, LAG3, and TIM3 pre- and post-treatment. Pre- indicates pre-treatment (blue circles; n = 22); Post1 indicates post-treatment, dose 1 (brown squares; n = 22); Post2 indicates post-treatment, dose 2 (pink triangles; n = 21). d, Categorical scatter plot showing frequency of ICOS + CD4 T cells pre- and post-treatment. Sample numbers and color schema same as in a-c. For a-d, error bars are shown as mean±standard deviation. e, Paired dot plots showing frequency of ICOS+ CD4 T cells in matched pre- and post-treatment (Post2) blood samples. NR indicates non-responders (n = 7); R indicates responders (n = 10). P values were calculated using the two-sided Wilcoxon rank-sum test in a-d and Wilcoxon signed-rank test in e. f, Representative multiplex immunofluorescence images (magnification; 20X) from one non-responder, NR (top) and one responder, R (bottom) patient at pre-treatment, Pre (left) and post-treatment, Post2 (right) time points. The samples were stained for the following markers: ICOS (red) and CD4 (green). Nuclei were stained with DAPI (blue). White arrows point to CD4 T cells expressing ICOS. Matched pre- and post-treatment samples from 10 patients (R = 5 and NR = 5) had similar analyses completed with corresponding images that were used to generate the data in g. g, Paired dot plots showing percentage of ICOS+CD4 T cells in matched pre- (blue circles) and post- (pink triangles) treatment tumor tissue samples from non-responders, NR (n = 5) and responders, R (n = 5). P values were calculated using the two-sided Wilcoxon rank-sum test. P < 0.05 is considered statistically significant.
Extended Data Fig. 7 Distribution of B cells, CD4 T cells, and CD8 T cells in pre-treatment tumor tissues of responders compared to non-responders.
a, Box plot showing density of B cells (CD20 + ) in pre-treatment tumor tissue samples from responders (R, n = 10) and non-responders (NR, n = 9). b, Box plot showing density of CD4 T cells in pre-treatment tumor tissue samples from responders (R, n = 10) and non-responders (NR, n = 9). c, Box plot showing density of CD8 T cells in pre-treatment tumor tissue samples from responders (R, n = 10) and non-responders (NR, n = 9). In the box plots, the horizontal bold line represents the median. The lower and upper hinges of the box correspond to the first and third quartiles (the 25th and 75th percentiles); the upper whisker extends from the hinge to the largest value no further than 1.5 × IQR from the hinge (where IQR is the distance between the first and third quartiles); and the lower whisker extends from the hinge to the smallest value at most 1.5 × IQR from the hinge. Statistical analysis was performed using two-sided Wilcoxon rank-sum test. P < 0.05 is considered statistically significant.
Extended Data Fig. 8 Association of POU2AF1 gene and TLS signature with response.
Pre-treatment tumor tissue samples from patients with TLS were analyzed by Nanostring. a, Box plot showing a comparison of POU2AF1 gene expression level between R (n = 9, red) and NR (n = 7, blue) patients. b, Box plot showing a comparison of 4-gene TLS signature derived from gene expression profiling of pre-treatment tumor tissue samples from R (n = 9, red) and NR (n = 7, blue) patients. In the box plots, the horizontal bold line represents the median. The lower and upper hinges of the box correspond to the first and third quartiles (the 25th and 75th percentiles); the upper whisker extends from the hinge to the largest value no further than 1.5 × IQR from the hinge (where IQR is the distance between the first and third quartiles); and the lower whisker extends from the hinge to the smallest value at most 1.5 × IQR from the hinge. P values were calculated using the two-sided unpaired student’s t–test, P < 0.05 is considered statistically significant.
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Gao, J., Navai, N., Alhalabi, O. et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat Med 26, 1845–1851 (2020). https://doi.org/10.1038/s41591-020-1086-y
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DOI: https://doi.org/10.1038/s41591-020-1086-y
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