Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going?
Abstract
:Simple Summary
Abstract
1. Introduction
2. Immune Checkpoint Inhibitors
3. Bladder/Urothelial Cancer
3.1. Non-Muscle-Invasive Bladder Cancer (NMIBC)
3.1.1. BCG
3.1.2. ICIs for NMIBC
3.2. Muscle-Invasive Bladder Cancer (MIBC)
3.2.1. Neoadjuvant Therapy for MIBC
3.2.2. Adjuvant Therapy for MIBC
3.2.3. Bladder-Sparing Treatments Involving ICIs in MIBC
3.3. Metastatic Bladder Cancer
3.3.1. Frontline Maintenance Therapy for Locally Advanced or Metastatic Bladder Cancer in Patients Who Previously Received Cisplatin Chemotherapy
3.3.2. Frontline Use in Combination with Chemotherapy
3.3.3. Frontline Use with Combination of Two ICIs
3.3.4. Frontline Use for Locally Advanced or Metastatic Cisplatin-Ineligible Patients
3.3.5. Second-Line Therapy for Locally Advanced or Metastatic Bladder Cancer Patients after Cisplatin Chemotherapy
3.4. Variant Histologic Subtypes of Urothelial Carcinoma and Response to ICIs
4. Kidney Cancer
4.1. Contemporary Frontline Therapies with ICIs
4.1.1. Combination of Two ICIs
4.1.2. Combination of ICI with Tyrosine Kinase Inhibitor
4.1.3. ICI Monotherapy
4.2. Second-Line Immunotherapy
4.3. Adjuvant Therapy after Nephrectomy
4.4. Non-Clear Cell Renal Cell Carcinoma
5. Prostate Cancer
6. Penile/Testicular/Adrenocortical Cancer
7. Potential Predictive Biomarkers for ICIs
8. Future Immune Checkpoint Inhibition Trials
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Trial | Agent(s) | Cancer Subtype and Disease Setting | Description | Original Food and Drug Administration Approval Date | Modifications |
---|---|---|---|---|---|
NCT02625961 (KEYNOTE-057) | Pembrolizumab monotherapy | Non-muscle-invasive bladder cancer | BCG refractory | January 2020 | |
NCT02632409 (CheckMate 274) | Nivolumab monotherapy | Muscle-invasive bladder cancer | Adjuvant therapy after radical resection | August 2021 | |
NCT02951767 (IMvigor210) | Atezolizumab monotherapy | Locally advanced or metastatic cisplatin-ineligible urothelial carcinoma | First-line metastatic | April 2017 (accelerated approval) | June 2018 (stricter guidelines including PD-L1 expression) |
NCT02335424 (KEYNOTE-052) | Pembrolizumab monotherapy | Locally advanced or metastatic cisplatin-ineligible urothelial carcinoma | First-line metastatic | August 2021 | |
NCT03288545 (EV-103/KEYNOTE-869) | Pembrolizumab and enfortumab vedotin | Locally advanced or metastatic cisplatin-ineligible urothelial carcinoma | First-line metastatic | February 2020 (breakthrough designation) | |
NCT02603432 (JAVELIN Bladder 100) | Avelumab monotherapy | Locally advanced or metastatic urothelial carcinoma | First-line maintenance after platinum-based chemotherapy | June 2020 | |
NCT02108652 (IMvigor210) | Atezolizumab monotherapy | Locally advanced or metastatic urothelial carcinoma after platinum therapy | Second-line metastatic | May 2016 (accelerated approval) | Withdrawal in March 2021 |
NCT02387996 (CheckMate 275) | Nivolumab monotherapy | Locally advanced or metastatic urothelial carcinoma after platinum therapy | Second-line metastatic | February 2017 (accelerated approval) | |
NCT02256436 (KEYNOTE-045) | Pembrolizumab monotherapy | Locally advanced or metastatic urothelial carcinoma after platinum therapy | Second-line metastatic | May 2017 | |
NCT01772004 (JAVELIN Solid Tumor) | Avelumab monotherapy | Locally advanced or metastatic urothelial carcinoma after platinum therapy | Second-line metastatic | May 2017 (accelerated approval) | |
NCT01693562 (Study 1108) | Durvalumab monotherapy | Locally advanced or metastatic urothelial carcinoma after platinum therapy | Second-line metastatic | May 2017 (accelerated approval) | Withdrawal in February 2021 |
NCT02853331 (KEYNOTE-426) | Pembrolizumab and axitinib | Metastatic renal cell carcinoma | First-line metastatic | April 2019 | |
NCT02684006 (JAVELIN Renal 101) | Avelumab and axitinib | Metastatic renal cell carcinoma | First-line metastatic | May 2019 | |
NCT0281186 (CLEAR) | Lenvatinib and pembrolizumab | Metastatic renal cell carcinoma | First-line metastatic | August 2021 | |
NCT03141177 (CheckMate 9ER) | Nivolumab and cabozantinib | Metastatic renal cell carcinoma | First-line metastatic | January 2021 | |
NCT02231749 (CheckMate 214) | Nivolumab and ipilimumab | Metastatic renal cell carcinoma | First-line metastatic | April 2018 | |
NCT01668784 (CheckMate 025) | Nivolumab | Metastatic renal cell carcinoma previously treated with angiogenic inhibitor | Second-line metastatic | November 2015 | |
NCT01876511 | Pembrolizumab | Tumors with high microsatellite instability or deficiency in mismatch repair refractory to other treatments | Progression on at least one prior systemic therapy | May 2017 (accelerated approval) | |
NCT02628067 (KEYNOTE-158) | Pembrolizumab | Tumors with high mutational burden refractory to other treatments | Progression on at least one prior systemic therapy | June 2020 (accelerated approval) |
Trial | Phase | Agent(s) | Bladder Cancer Stage | mOS | mPFS | ORR |
---|---|---|---|---|---|---|
NCT02625961 (KEYNOTE-057) [11] | 1 | Pembrolizumab monotherapy | Non-muscle-invasive bladder cancer after BCG treatment | NR | NR | - * |
NCT02632409 (CheckMate 274) [12] | 3 | Adjuvant nivolumab vs. control | Muscle-invasive bladder cancer after radical surgery | - | - | - ** |
NCT02603432 (JAVELIN Bladder 100) [13] | 3 | Avelumab monotherapy vs. control | Locally advanced or metastatic urothelial carcinoma | 21.4 vs. 14.3 months (HR 0.69; 95% CI, 0.56–0.86; p = 0.001) | 3.7 vs. 2.0 months (HR 0.62; 95% CI, 0.52–0.75; p < 0.001) | 9.7 vs. 1.4% (NA) |
NCT02951767 (IMvigor210) [14,15] | 2 | Atezolizumab monotherapy | Locally advanced or metastatic cisplatin-ineligible urothelial cancer | 16.3 months (95% CI, 10.4–24.5) | 2.7 months (95% CI, 2.1–4.2) | 24% (95% CI, 16–32) |
NCT02335424 (KEYNOTE-052) [16,17] | 2 | Pembrolizumab monotherapy | Locally advanced or metastatic cisplatin-ineligible urothelial cancer | 11.3 months (95% CI, 9.7–13.1) | 2.2 months (95% CI, 2.1–3.4) | 28.6% (95% CI, 24.1–33.5) |
NCT03288545 (EV-103/KEYNOTE-869) [18] | 1/2 | Pembrolizumab and enfortumab vedotin | Locally advanced or metastatic cisplatin-ineligible urothelial cancer | - | 12.3 months (95% CI, 7.98–NR) | 73.3% (95% CI, 58.1–85.4) |
NCT02108652 (IMvigor210) [19] | 2 | Atezolizumab monotherapy | Locally advanced or metastatic urothelial carcinoma after platinum therapy | 7.9 months (95% CI, 6.6–9.3) | 2.1 months (95% CI, 2.1–2.1) | 15% (95% CI, 11–19) |
NCT02387996 (CheckMate 275) [20,21] | 2 | Nivolumab monotherapy | Locally advanced or metastatic urothelial carcinoma after platinum therapy | 8.6 months (95% CI, 6.1–11.3) | 1.9 months (95% CI, 1.9–2.3) | 20.7% (95% CI, 16.1–26.1) |
NCT02256436 (KEYNOTE-045) [22,23] | 3 | Pembrolizumab monotherapy vs. control | Locally advanced or metastatic urothelial carcinoma after platinum therapy | 10.1 vs. 7.3 months (HR 0.70; 95% CI, 0.57–0.85; p < 0.001) | 2.1 vs. 3.3 months (HR 0.96; 95% CI, 0.79–1.16; p = 0.313) | 21.1 vs. 11.0% (NA) |
NCT01772004 (JAVELIN Solid Tumor) [24,25] | 1 | Avelumab monotherapy | Locally advanced or metastatic urothelial carcinoma after platinum therapy | 7.0 months (95% CI, 5.9–8.5) | 1.6 months (95% CI, 1.4–2.7) | 16.5% (95% CI, 12.1–21.8) |
NCT01693562 (Study 1108) [26,27] | 1 | Durvalumab monotherapy | Locally advanced or metastatic urothelial carcinoma after platinum therapy | 18.2 months (95% CI, 8.1–NE) | 1.5 months (95% CI, 1.4–1.9) | 17.8% (95% CI, 12.7–24.0) |
Trial | Phase | Agent(s) | RCC Stage | mOS | mPFS | ORR (p-Value) |
---|---|---|---|---|---|---|
NCT02231749 (CheckMate 214) [76,77] | 3 | Nivolumab and ipilimumab versus sunitinib | Metastatic renal cell carcinoma | 48.1 vs. 26.6 months (HR 0.65; 95% CI, 0.54–0.78) * | 11.2 vs. 8.3 months (HR 0.74; 95% CI, 0.62–0.88) * | 41.9 vs. 26.8% (p < 0.0001) * |
NCT02853331 (KEYNOTE-426) [78,79] | 3 | Pembrolizumab with axitinib versus sunitinib | Metastatic renal cell carcinoma | NR vs. 35.7 months (HR 0.68; 95% CI, 0.55–0.85; p = 0.0003) | 15.4 vs. 11.1 months (HR 0.71; 95% CI, 0.60–0.84; p < 0.0001) | 60 vs. 40% (p < 0.001) |
NCT02501096 (CLEAR) [80] | 3 | Lenvatinib with pembrolizumab versus sunitinib | Metastatic renal cell carcinoma | NR vs. NR (HR 0.66; 95% CI, 0.49–0.88; p = 0.005) | 23.9 vs. 9.2 months (HR 0.39; 95% CI, 0.32–0.49; p < 0.001) | 71.0% vs. 36.1% (NA) |
NCT03141177 (CheckMate 9ER) [81] | 3 | Nivolumab and cabozantinib versus sunitinib | Metastatic renal cell carcinoma | NR vs. NR (HR 0.60; 98.89% CI, 0.40–0.89; p = 0.001) | 16.6 vs. 8.3 months (HR 0.51; 95% CI, 0.41–0.64; p < 0.001) | 55.7% vs. 27.1% (p < 0.001) |
NCT02684006 (JAVELIN Renal 101) [82,83] | 3 | Avelumab with axitinib versus sunitinib | Metastatic renal cell carcinoma | NR vs. NR (HR 0.80; 95% CI, 0.62–1.03; p = 0.0392) | 13.3 vs. 8.0 months (HR 0.69; 95% CI, 0.57–0.83; p < 0.0001) | 52.5% vs. 27.3% (NA) |
NCT02420821 (IMmotion151) [84] | 3 | Atezolizumab with bevacizumab versus sunitinib | Metastatic renal cell carcinoma | 33.6 vs. 34.9 months (HR 0.93; 95% CI, 0.76–1.14; p = 0.4751) | 11.2 vs. 8.4 months (HR 0.83; 95% CI, 0.70–0.97; p = 0.0219) | 37% vs. 33% (NA) |
NCT01668784 (CheckMate 025) [85,86] | 3 | Nivolumab versus everolimus | Metastatic renal cell carcinoma previously treated with angiogenic inhibitor | 25.8 vs. 19.7 months (HR 0.73; 95% CI, 0.62–0.85; p < 0.001) | 4.2 vs. 4.5 months (HR 0.84; 95% CI, 0.72–0.99; p = 0.0331) ** | 23% vs. 4% (p < 0.001) |
Trial | Phase | Setting | Intervention | Comparator | Sample Size |
---|---|---|---|---|---|
Bladder | |||||
NCT04223856 | 3 | 1st line | Pembrolizumab, EV | Gemcitabine, cisplatin | 760 |
NCT03682068 | 3 | 1st line | Durvalumab, tremelimumab, chemotherapy | Chemotherapy | 1292 |
NCT03036098 | 3 | 1st line | Nivolumab, ipilimumab or nivolumab, chemotherapy | Chemotherapy | 1290 |
NCT03898180 | 3 | 1st line | Pembrolizumab, lenvatinib | Pembrolizumab, placebo | 694 |
NCT03601455 | 2 | 1st line | Durvalumab, tremelimumab, radiation | Durvalumab, radiation | 13 |
NCT03606174 | 2 | 1st line | Nivolumab, pembrolizumab, EV, sitravatinib | 425 | |
NCT03534804 | 2 | 1st line | Pembrolizumab, cabozantinib | 39 | |
NCT03785925 | 2 | 1st line | Nivolumab, bempegaldesleukin | 192 | |
NCT03288545 | 1/2 | 1st or 2nd line | Pembrolizumab, EV, chemotherapy | 457 | |
NCT03854474 | 1/2 | 1st or 2nd line | Pembrolizumab, tazemetostat | 30 | |
NCT04045613 | 1/2 | 1st or ≥2nd line | Atezolizumab, derazantinib | 272 | |
NCT04953104 | 2 | ≥2nd line | Nivolumab | 30 | |
NCT04101812 | 2 | 2nd line | PD-1 ICI, doxorubicin | PD-1 ICI | 60 |
NCT02717156 | 2 | 2nd line | Pembrolizumab, sEphB4-HSA | 60 | |
NCT04004442 | 1/2 | 2nd line | Avelumab, AVB-S6-500 | 31 | |
NCT03179943 | 2 | ≥2nd line | Atezolizumab, guadecitabine | 21 | |
NCT03547973 | 2 | ≥2nd line | Pembrolizumab, SG, avelumab, cisplatin | 321 | |
NCT03513952 | 2 | ≥2nd line | Atezolizumab, CYT107 | 54 | |
Kidney | |||||
NCT03793166 | 3 | 1st line | Nivolumab, ipilimumab then nivolumab, cabozantinib | Nivolumab, ipilimumab then nivolumab | 1046 |
NCT03937219 | 3 | 1st line | Nivolumab, ipilimumab, cabozantinib | Nivolumab, ipilimumab, placebo | 840 |
NCT03729245 | 3 | 1st line | Nivolumab, bempegaldesleukin | Sunitinib or cabozantinib | 623 |
NCT03977571 | 3 | 1st line ** | Nivolumab, ipilimumab, nephrectomy | Nivolumab, ipilimumab | 400 |
NCT04510597 | 3 | 1st line ** | ICI with/without axitinib, nephrectomy | ICI | 364 |
NCT04338269 | 3 | 2nd line ** | Atezolizumab, cabozantinib | Cabozantinib | 500 |
NCT04987203 | 3 | 2nd or 3rd line | Nivolumab, tivozanib | Tivozanib | 326 |
NCT03117309 | 2 | 1st line ** | Nivolumab and salvage nivolumab, ipilimumab | 134 | |
NCT04704219 | 2 | 1st line * | Pembrolizumab, lenvatinib | 152 | |
NCT04267120 | 2 | 1st line * | Pembrolizumab, lenvatinib | 34 | |
NCT03075423 | 2 | 1st line * | Nivolumab, ipilimumab | Sunitinib | 306 |
NCT04644432 | 2 | 1st line * | Pembrolizumab or nivolumab | 30 | |
NCT03177239 | 2 | ≥1st line * | Nivolumab, then nivolumab, ipilimumab | 85 | |
NCT04413123 | 2 | ≥1st line * | Nivolumab, ipilimumab, cabozantinib | 40 | |
NCT03274258 | 2 | ≥1st line * | Nivolumab, ipilimumab | 10 | |
NCT03595124 | 2 | TFE/tRCC | Nivolumab, axitinib | Nivolumab | 70 |
NCT04385654 | 2 | Neoadjuvant * | Toripalimab, axitinib | 40 | |
NCT02724878 | 2 | ≥1st line * | Atezolizumab, bevacizumab | 65 | |
NCT03297593 | 2 | 1st or 2nd line | Nivolumab, ipilimumab | 74 | |
NCT04698213 | 2 | 1st line | Avelumab, axitinib | 75 | |
NCT04338269 | 3 | ≥2nd line ** | Atezolizumab, cabozantinib | Cabozantinib | 500 |
NCT03469713 | 2 | 2nd or 3rd line | Nivolumab, SBRT | 69 | |
NCT03149822 | 1/2 | ICI eligible | Pembrolizumab, cabozantinib | 45 | |
NCT04758507 | 1/2 | ICI eligible | ICI, microbiota transplant | ICI, placebo transplant | 50 |
Prostate | |||||
NCT04191096 | 3 | mHSPC | Pembrolizumab, enzalutamide, ADT | Placebo, enzalutamide, ADT | 1232 |
NCT03879122 | 2/3 | mHSPC | Nivolumab, ipilimumab, docetaxel, ADT | Docetaxel, ADT | 135 |
NCT04126070 | 2 | mHSPC | Nivolumab, docetaxel, ADT | 60 | |
NCT04633252 | 1/2 | mCRPC, mHSPC | M7824, M9241, docetaxel, ADT | 86 | |
NCT04104893 | 2 | mCRPC | Pembrolizumab | 30 | |
NCT03506997 | 2 | mCRPC | Pembrolizumab | 100 | |
NCT04116775 | 2 | mCRPC | Pembrolizumab, microbiota transplant, enzalutamide | 32 | |
NCT03406858 | 2 | mCRPC | Pembrolizumab, HER2Bi-armed activated T cells | 33 | |
NCT03040791 | 2 | mCRPC | Nivolumab | 38 | |
NCT04717154 | 2 | mCRPC | Nivolumab, ipilimumab | 75 | |
NCT03570619 | 2 | mCRPC | Nivolumab, ipilimumab | 40 | |
NCT03554317 | 2 | mCRPC | Nivolumab, BAT | 44 | |
NCT04089553 | 2 | mCRPC | Durvalumab, oleclumab, AZD4635 | 58 | |
NCT04926181 | 2 | mCRPC | Cetrelimab, apalutamide | 24 | |
NCT03910660 | 1/2 | mCRPC | Pembrolizumab, talabostat mesylate | 40 | |
NCT02861573 | 1/2 | mCRPC | Pembrolizumab combination therapies | 1000 | |
NCT02484404 | 1/2 | mCRPC | Olaparib, cediranib, durvalumab | 384 | |
NCT04381832 | 1/2 | mCRPC | Zimberelimab combination therapies | 140 | |
NCT03673787 | 1/2 | mCRPC | Atezolizumab, ipatasertib | 87 | |
NCT05000294 | 1/2 | mCRPC | Atezolizumab, tivozanib | 29 | |
Rare tumors | |||||
NCT03427411 | 2 | HPV-associated disease | M7824 | 57 | |
NCT02834013 | 2 | 2nd line | Ipilimumab, nivolumab | 818 | |
NCT02721732 | 2 | ≥2nd line | Pembrolizumab | 225 | |
NCT03333616 | 2 | Advanced disease | Ipilimumab, nivolumab | 100 | |
NCT03866382 | 2 | Advanced disease | Cabozantinib, ipilimumab, nivolumab | 224 | |
NCT04400474 | 2 | Advanced disease | Cabozantinib, atezolizumab | 144 | |
NCT04187404 | 1/2 | Advanced disease | Nivolumab, EO2401 | 60 |
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Jang, A.; Adler, D.M.; Rauterkus, G.P.; Bilen, M.A.; Barata, P.C. Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going? Cancers 2021, 13, 5065. https://doi.org/10.3390/cancers13205065
Jang A, Adler DM, Rauterkus GP, Bilen MA, Barata PC. Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going? Cancers. 2021; 13(20):5065. https://doi.org/10.3390/cancers13205065
Chicago/Turabian StyleJang, Albert, David M. Adler, Grant P. Rauterkus, Mehmet A. Bilen, and Pedro C. Barata. 2021. "Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going?" Cancers 13, no. 20: 5065. https://doi.org/10.3390/cancers13205065