Table 1.
Clinical trials of atezolizumab for urothelial carcinoma
| Trial | Status/estimated primary completion date | Phase/characteristics | Disease setting/type of therapy | Treatment arms/number of patients | PDL1 positivity | Primary/secondary/tertiary outcomes | ORR (95% CI) | Median PFS, months (95% CI) | Median OS, months (95% CI) |
|---|---|---|---|---|---|---|---|---|---|
| NCT0137584228,37 (PCD4989g) | Completed | Phase I/open-label dose escalation for solid and hematologic malignancies (including a UCB cohort) | Patients with locally advanced and metastatic solid tumors and hematological malignancies/second-line therapy | Atezolizumab, IV infusion q3w up to 20 mg/kg (15 mg/kg for UCB cohort)/total of 604 patients to be enrolled, 68 patients included in expansion cohort of mUCB | IHC, positive if ≥5% of PDL1 positive IC/TC Score: IHC0, <1%; IHC1, ≥1% but <5%; IHC2, ≥5% but <10%; IHC3, ≥10% of IC and TC with PDL1 |
Incidence and nature of DLT and AEs (for UCB cohort; antitumor activity as well) | IHC1/0: 11% (4%–26%) IHC2/3: 43% (26%–63%) |
NA | NA |
| NCT0295176745,46 (IMvigor210) | Completed | Phase II/nonrandomized, open-label | Treatment-naïve cisplatin-ineligible patients (group 1)/first-line therapy | Atezolizumab, IV infusion 1,200 mg q3w/119 patients included | IHC, only IC, not TC Score: IC0 <1% IC1.=1% but <5% IC2/3 >=5% of IC with PDL1 |
ORR according to RECIST 1.1 and irRECIST/DOR, PFS according to RECIST 1.1 and irRECIST, OS and safety | Overall: 24% (16%–32%) IC1/2/3: 25% (16%–36%) IC2/3: 28% (14%–47%) |
NA | Overall: 14.8 (10.1–NR) IC0/1: 15.3 (9.8–NR) IC2/3: 12.3 (6.0–NR) |
| NCT0210865212,43 (IMvigor210) | Completed | Phase II/nonrandomized, open-label | Patients with progression during or following prior platinum-based chemotherapy (group 2)/second-line therapy | Atezolizumab, IV infusion 1,200 mg q3w/310 patients included | IHC, only IC, not TC Score: IC0 <1% IC1 >=1% but <5% IC2/3 >=5% of IC with PDL1 |
ORR according to RECIST 1.1 and irRECIST/DOR, PFS according to RECIST 1.1 and irRECIST, OS and safety | Overall: 15% (11%–20%) IC1/2/3: 18% (13%–24%) IC2/3: 27% (19%–37%) |
Overall: 2.7 (2.1–3.9) IC1/2/3: 2.9 (2.1–4.1) IC2/3: 4.0 (2.6–5.9) by irRECIST |
Overall: 7.9 (6.6–9.3) IC0: 6.5 (4.4–8.3) IC1: 6.7 (5.1–8.8) IC2/3: 11.4 (9.0–NR) |
| NCT0230280747,48 (IMvigor211) | Mid-2017 | Phase III/randomized, open-label | Patients with locally advanced or metastatic UCB after failure of platinum-containing chemotherapy/second-line therapy | 1) Atezolizumab IV infusion 1,200 mg q3w; 2) vinflunine, paclitaxel, or docetaxel IV infusion 320 mg, 175 mg, or 75 mg/m2 q3w/total of 932 patients to be enrolled |
Not defined | OS/ORR, PFS, DOR, AEs, percentage of patients with ATA, Cmax, Cmin, EORTC QLQ-C30 | NA | NA | NA |
| NCT0280763649 (IMvigor130) | June 2020 | Phase III/randomized, placebo-controlled, double-blind | Patients with locally advanced or metastatic UCB who have not received prior systemic therapy and who are ineligible to receive cisplatin-based therapy/first-line therapy | 1) Atezolizumab IV infusion 1,200 mg q3w and carboplatin at dose AUC of 4.5 mg/mL·min and gemcitabine IV infusion 1,000 mg/m2 on day 1 and day 8 of each 21-day cycle; 2) placebo IV infusion q3w (in combination with gemcitabine/carboplatin, dosed as described above)/total of 435 patients to be enrolled |
Not defined | PFS assessed by investigator using RECIST 1.1, OS and percentage of AEs/ORR, DOR, PFS assessed by independent review facility using RECIST 1.1, percentage of patients with ATA, median time to deterioration | NA | NA | NA |
| NCT0245033150 (IMvigor010) | April 2022 | Phase III/randomized, open-label | Patients with PDL1-positive, high-risk muscle-invasive bladder cancer after cystectomy/adjuvant therapy | 1) Atezolizumab IV infusion 1,200 mg q3w for 16 cycles or 1 year; 2) observation q3w for 16 cycles or 1-year alternating clinic visit/phone call/total of 700 patients to be enrolled |
Positive | DFS/OS, CSS, DMFS, AEs, percentage of ATA response, Cmax | NA | NA | NA |
| NCT0279219251 (WO29635) | November 2020 | Phase IB/II/nonrandomized, open-label | Patients with high-risk non-muscle-invasive bladder cancer after failure of BCG or BCG-naïve/first-line and second-line therapy | 1A) BCG-unresponsive NMIBC, atezolizumab IV infusion q3w for a maximum of 32 doses or 96 weeks of therapy; 1B) BCG-unresponsive NMIBC, during BCG-maintenance courses 2–5 (every 24 weeks), atezolizumab 1,200 mg IV infusion q3w for a total of eight doses per course up to 96 weeks; 2) BCG-relapsing NMIBC, during BCG-maintenance courses 2–5 (every 24 weeks), atezolizumab 1,200 mg IV infusion q3w for a total of eight doses per course up to 96 weeks; 3) BCG-naïve NMIBC, during BCG-maintenance courses 2–5 (every 24 weeks), atezolizumab 1,200 mg IV infusion q3w for a total of 8 doses per course up to 96 weeks/total of 70 patients to be enrolled |
Not defined | AEs, complete response assessed by investigator on basis of cystoscopy and urine cytology/bladder-intact DFS, PFS, cystectomy-free survival, OS, C max, Cmin | NA | NA | NA |
| NCT0266230952 (ABACUS) | March 2017 | Phase II/single-group assignment, open-label | Patients with histologically confirmed (T2–T4a) UCB/neoadjuvant therapy | Two 3-weekly cycles of MPDL3280A (one infusion on the first day of each cycle) prior to cystectomy/total of 85 patients to be enrolled | Not defined | Pathological complete-response rate and effect on immune parameters/safety, tolerability, radiological response, DFS, OS | NA | NA | NA |
| NCT0245142353 (14524) | December 2019 | Phase II/single-group assignment, open-label | Patients with either BCG-refractory NMIBC or muscle-invasive UCB appropriate for cystectomy and refusing or ineligible for neoadjuvant chemotherapy/neoadjuvant therapy | MPDL3280A IV q3w, dose escalations from one to three doses: 1a) 1,200 mg ×1 dose; 1b) 1,200 mg ×2 doses; 1c) 1,200 mg ×3 doses/total of 42 patients to be enrolled | Any | Change in CD3+ T-cell count, pathological T0 rate/AEs, percentage of treatment-related delay in surgery | NA | NA | NA |
| NCT0284481654 (S1605) | February 2019 | Phase II/single-group assignment, open-label | BCG-unresponsive patients with non-muscle-invasive bladder cancer/second-line therapy | Atezolizumab IV q3w for up to 16 courses (48 weeks)/total of 143 patients to be enrolled | Not defined | Event-free survival/CSS, complete response rate in patients with CIS, AEs, OS/expression of PDL1, CD8, other markers, immunosignatures by RNA sequencing, neoantigen burden by whole-exome sequencing, mismatch-repair deficiency, circulating IC by flow cytometry | NA | NA | NA |
| NCT0265582255 (CPI-444-001) | June 2018 | Phase I/IB/randomized, open-label | Incurable non-small-cell lung cancer, malignant melanoma, renal cell cancer, head and neck cancer, triple-negative breast cancer, colorectal cancer, and bladder cancer/second line therapy and beyond | 1) CPI-444, 100 mg orally twice for the first 14 days of each 28-day cycle; 2) CPI-444, 100 mg orally twice for 28 days of each 28-day cycle; 3) CPI-444, 200 mg orally once daily for the first 14 days of each 28-day cycle; 4) CPI-444+ atezolizumab IV, CPI-444 orally in combination with IV atezolizumab/total of 534 patients to be enrolled, including all tumor types |
Not defined | DLT, ORR, AE, AUC of CPI-444, Cmax of CPI-444 | NA | NA | NA |
| NCT0254364556 (CDX1127-06) | December 2017 | Phases I//II/single-group assignment, open-label | Unresectable solid tumors; Phase I, melanoma, renal cell cancer, triple-negative breast cancer, bladder cancer, non-small-cell lung cancer, head and neck cancer; Phase II, renal cell cancer/second line therapy and beyond | Phase I, varlilumab doses at 0.3, 1, and 3 mg/kg (dose escalations) +1,200 mg IV atezolizumab; Phase II, varlilumab dose will be established upon outcomes of Phase I study +1,200 mg IV atezolizumab/up to 18 and 37 patients to be enrolled for Phases I and II trials, respectively, including all tumor types | Not defined | Phase I, safety, tolerability, AEs, DLT; Phase II, ORR | NA | NA | NA |
| NCT0163397057 (GP28328) | December 2018 | Phase IB/randomized, open-label | Locally advanced and metastatic solid tumors: renal cell cancer, triple-negative breast cancer, bladder cancer, non-small-cell lung cancer, ovarian cancer, gastric cancer, cervical cancer, prostate cancer/second-line therapy and beyond | 1) Atezolizumab + bevacizumab 10 mg/kg IV atezolizumab with bevacizumab 15 mg/kg q3w, followed by dose escalation; 2) atezolizumab + bevacizumab + FOLFOX (oxaliplatin/leucovorin/5-FU; oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 400 mg/m2 [day 1 of cycle 1]), then atezolizumab 800 mg IV q2w, bevacizumab 10 mg/kg IV q3w, and FOLFOX q2w (day 1 of all subsequent cycles); 3) atezolizumab + carboplatin + paclitaxel (1,200 mg IV atezolizumab q3w + paclitaxel 200 mg/m2 IV q3w, then carboplatin IV q3w [day 1 of every 3-week cycle]) to achieve AUC of 6 mg/mL·min; 4) atezolizumab + carboplatin + pemetrexed (1,200 mg IV atezolizumab q3w + pemetrexed 500 mg/m2 IV q3w, then carboplatin IV q3w [day 1 of every 3 week cycle]) to achieve AUC of 6 mg/mL·min; 5) atezolizumab + carboplatin + nab-paclitaxel (1,200 mg IV atezolizumab q3w [day 1 of every 3-week cycle] + nab-paclitaxel 100 mg/m2 IV qw [days 1, 8, and 15 of every 3-week cycle], then carboplatin IV q3w [day 1 of every 3-week cycle] to achieve AUC of 6 mg/mL·min; 6) atezolizumab + nab-paclitaxel (800 mg IV atezolizumab q2w [days 1 and 15] + nab-paclitaxel 125 mg/m2 IV qw [days 1, 8, and 5 of every 3-week cycle])/total of 235 patients to be enrolled, including all tumor types |
Not defined | Maximum tolerated dose, AEs, DLT/DOR, PFS according to RECIST 1.1 and irRECIST, pharmacokinetics, Cmin, OR | NA | NA | NA |
| NCT0229815358 (ECHO-110) | October 2019 | Phase I/single-group assignment, open-label | Locally advanced non-small-cell lung carcinoma and stage IV locally advanced urothelial carcinoma or mUCB patients who failed platinum-based chemotherapy/second-line therapy and beyond | Atezolizumab + epacadostat (INCB024360): IV 1,200 mg atezolizumab q3w + epacadostat 25 mg BID as starting dose, followed by dose escalations/total of 118 patients to be enrolled, including all tumor types | Not defined | AE, DLT/ORR, DOR, PFS/biomarker expression by expansion cohort | NA | NA | NA |
Abbreviations: AEs, adverse events; CI, confidence interval; UCB, urothelial carcinoma of bladder; CIS, carcinoma in situ; DFS, disease-free survival; DLT, dose-limiting toxicity; IC, immune cell (tumor-infiltrating); TC, tumor cell; IHC, immunohistochemistry; DOR, duration of response; irRECIST, immune-related RECIST; CSS, cancer-specific survival; NA, not available; NR, not reached; q3w, every 3 weeks; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; DMFS, distant metastasis-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; ATA, antitherapeutic antibodies; EORTC, European Organisation for Research and Treatment of Cancer; QLQ-C30, Quality-of-Life Questionnaire Core 30; Cmax, maximum concentration; Cmin, minimum concentration; AUC, area under the (concentration–time) curve; NMIBC, non-muscle-invasive bladder cancer; BCG, bacillus Calmette–Guérin; mUCB, metastatic urothelial carcinoma of the bladder.