Neoadjuvant pembrolizumab plus gemcitabine with or without cisplatin led to high rates of downstaging to non–muscle invasive urothelial cancer in patients with muscle-invasive urothelial cancer, meeting the primary end points for both cohorts of the phase 1b/2 HCRN GU14-188 trial.
Neoadjuvant pembrolizumab (Keytruda) plus gemcitabine with or without cisplatin led to high rates of downstaging to non–muscle invasive urothelial cancer in patients with muscle-invasive urothelial cancer, meeting the primary end points for both cohorts of the phase 1b/2 HCRN GU14-188 trial (NCT02365766), according to findings presented at the 2023 Genitourinary Cancers Symposium.
At a median follow-up of 54.8 months (range, 2.2-67.0) in patients who received cisplatin, gemcitabine, and pembrolizumab and 29.2 months (range, 1.5-62.6) in those who received gemcitabine plus pembrolizumab, the pathologic muscle-invasive response rates (PalR) were 61% (95% CI, 45%-75%) and 52% (95% CI, 35%-68%), respectively.1
“There is a shown synergy between immunotherapy and chemotherapy, including increased antigen presentation, as well as breaking immune tolerance,” lead study author Jason Brown, MD, PhD, of University Hospitals Seidman Cancer Center in Cleveland, Ohio, said in a presentation of the data.
Previously, a single-arm phase 2 trial (NCT02690558) demonstrated that the combination of neoadjuvant pembrolizumab, gemcitabine, and split-dose cisplatin elicited a pathologic downstaging rate of 56% and a pT0N0 rate of 36% in patients with clinical stage T2-4a muscle-invasive bladder cancer eligible for radical cystectomy.2 The HCRN GU14-188 trial aimed to evaluate the efficacy and safety of immunotherapy plus chemotherapy in both cisplatin-eligible and cisplatin-ineligible patients with muscle-invasive bladder cancer.
To be eligible for HCRN GU14-188, patients needed to be surgical candidates with histologically confirmed, node-negative, nonmetastatic muscle-invasive bladder, pelvis, or ureter cancer of clinical stage cT2-4a.1 Patients were also required to have available tissue for PD-L1 staining, adequate organ function, no known active additional malignancies, and no heart failure, autoimmune disease, HIV, interstitial lung disease, pneumonitis, or active hepatitis B or C. Patients could not have received corticosteroids at over 10 mg per day within 7 days prior to enrollment.
This study enrolled 43 patients with cisplatin-eligible muscle-invasive urothelial carcinoma to receive neoadjuvant cisplatin plus gemcitabine and pembrolizumab (cohort A) and 38 patients with cisplatin-ineligible disease to receive neoadjuvant gemcitabine plus pembrolizumab (cohort B). Patients in cohort A received 4, 21-day cycles of cisplatin plus gemcitabine, and the cisplatin dose could be split between days 1 and 8 in patients with a creatinine clearance of 50 to 59 mL/min, Brown noted in the presentation. Patients in cohort B received 3, 28-day cycles of gemcitabine. Patients in both cohorts received pembrolizumab every 3 weeks beginning on day 8 of cycle 1.
The primary end point of this trial was PalR rate, defined by Brown as the rate of pathologic downstaging to non–muscle invasive bladder cancer, with null hypotheses of 23% PaIR rate in cohort A and 18% PaIR rate in cohort B. Secondary end points included ypT0N0 rate, 18-month relapse-free survival (RFS) rate, 36-month overall survival (OS) rate, and the rate of patients who received definitive surgery, either radical cystectomy or nephroureterectomy.
In cohort A, the median age was 64 years (range, 42-77), 73.8% (n = 31) of patients were male, 83.3% (n = 35) of patients were White, and 42.9% (n = 18) of patients had muscle-invasive urothelial carcinoma greater than stage T2 at diagnosis. Patients in cohort A received a median of 5 cycles of pembrolizumab (range, 1-5) and a median of 4 cycles of gemcitabine plus cisplatin (range, 2-4), and had a median time to surgery of 130 days (range, 81-186).
In cohort B, the median age was 73 years (range, 58-83), 71.8% (n = 28) of patients were male, 92.3% (n = 36) of patients were White, and 61.5% (n = 24) of patients had disease greater than stage T2 at diagnosis. Patients in this cohort received a median of 5 cycles of pembrolizumab (range, 1-6) and a median of 3 cycles of gemcitabine plus cisplatin (range, 1-3), and had a median time to surgery of 128 days (range, 11-226).
In cohorts A and B, the ypT0N0 rates were 44% (95% CI, 29%-61%) and 45% (95% CI, 31%-61%), respectively, and the surgery rates were 88% (95% CI, 72%-93%) and 87% (95% CI, 73%-94%), respectively.
The 18-month RFS rates were 82% (95% CI, 66%-91%) and 65% (95% CI, 48%-78%) in cohorts A and B, respectively. The 36-month OS rates were 79% (95% CI, 65%-90%) and 66% (95% CI, 47%-79%) in cohorts A and B, respectively.
“These data are still not quite mature, but the tails at the ends of these survival curves indicate a durable response to treatment,” Brown noted.
Across both cohorts, the reported adverse effects were anemia (any grade, 72.8%; grade ≥ 3, 29.6%), anorexia (any grade, 49.4%; grade ≥ 3, 4.9%), thrombocytopenia (any grade, 44.4%; grade ≥ 3, 8.6%), neutropenia (any grade, 43.2%; grade ≥ 3, 24.7%), hypertension (any grade, 40.7%; grade ≥ 3, 28.3%), dyspnea (any grade, 40.7%; grade ≥ 3, 3.7%), elevated liver enzymes (any grade, 35.8%; grade ≥ 3, 3.7%), rash (any grade, 27.2%; grade ≥ 3, 2.5%), urinary tract infection (any grade, 24.7%; grade ≥ 3, 7.4%), hyponatremia (any grade, 16.0%; grade ≥ 3, 8.6%), thromboembolic events (any grade, 14.8%; grade ≥ 3, 8.6%), thyroid disorders (any grade, 12.3%; grade ≥ 3, 0%), acute kidney injuries (any grade, 8.6%; grade ≥ 3, 4.9%), hypokalemia (any grade, 8.6%; grade ≥ 3, 4.9%), sepsis (any grade, 7.4%; grade ≥ 3, 7.4%), colitis (any grade, 4.9%; grade ≥ 3, 2.5%), and pneumonitis (any grade, 3.7%; grade ≥ 3, 2.5%).
“In both cohorts, treatment with chemoimmunotherapy was well tolerated, and ongoing studies will further evaluate the efficacy of chemoimmunotherapy in muscle-invasive urothelial cancer,” Brown concluded.
Editor’s Note: Dr Brown reports honoraria from AstraZeneca; Speaker’s Bureau participation with EMD Serono; and research funding from Bicycle Therapeutics (Inst), Jounce Therapeutics (Inst), Merck (Inst), Novita Pharmaceuticals (Inst), and Seagen (Inst).