Nivolumab Plus Gemcitabine/Cisplatin Shows Favorable OS/PFS Trend in Asian Unresectable/Metastatic Urothelial Cancer Subpopulation

Nivolumab (Opdivo) plus gemcitabine and cisplatin demonstrated a trend toward improved overall survival (OS) and progression-free survival (PFS) compared with gemcitabine and cisplatin alone as first-line treatment in patients with previously untreated unresectable or metastatic urothelial cancer, according to findings from the Asian population analysis of the phase 3 CheckMate 901 trial (NCT03036098) presented at the 2024 ESMO Asia Congress.1

At a median study follow-up of 27.2 months (range, 7.6-62.4) in the Asian subpopulation, events occurred in 36 and 34 patients from the nivolumab plus gemcitabine/cisplatin (n = 72) and gemcitabine/cisplatin (n = 61) arms, respectively. The median OS in the nivolumab plus gemcitabine/cisplatin and gemcitabine/cisplatin arms was 24.0 months (95% CI, 19.0-28.9) and 18.9 months (95% CI, 12.0-24.9), respectively (HR, 0.69; 95% CI, 0.42-1.15).

Regarding PFS, patients in the Asian subpopulation experienced 43 and 33 events in the combination and gemcitabine/cisplatin alone arms, respectively. The median PFS was 9.5 months (95% CI, 7.6-11.2) and 7.2 (95% CI, 5.7-7.8) in the investigational and control arms, respectively (HR, 0.53; 95% CI, 0.32-0.88).

“In the Asian subpopulation of CheckMate 901, nivolumab plus gemcitabine/cisplatin showed trends toward improved OS and PFS vs gemcitabine/cisplatin alone as a first-[line] treatment for [patients with] unresectable and metastatic urothelial cancer, not only for bladder cancer but also upper tract urothelial cancer [UTUC],” lead study author Yoshihiko Tomita, MD, PhD, director, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan, said during an oral presentation at the meeting.

Nivolumab Combination Background and CheckMate 901 Study Design

The FDA approved the combination of nivolumab with gemcitabine and cisplatin in March 2024 for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma.2 The approval was based on efficacy findings from the phase 3 CheckMate 901 study, which evaluated OS and PFS in the combination vs gemcitabine and cisplatin arms.

The phase 3, open-label, randomized CheckMate 901 study enrolled patients with previously untreated unresectable or metastatic urothelial carcinoma that involved the renal pelvis, ureter, bladder, or urethra.1 Patients were required to be at least 18 years of age, cisplatin eligible, and have an ECOG performance status of 0 or 1. The study compared chemotherapy with or without nivolumab in patients with bladder cancer and UTUC, as the proportion of UTUC in urothelial carcinoma overall is higher in Asia than in the rest of the world.3

Patients enrolled were randomly assigned to the nivolumab plus gemcitabine and cisplatin arm (global, n = 304; Asian, n = 72) or the gemcitabine and cisplatin alone arm (global, n = 304; Asian, n = 61). Those in the combination arm received 360 mg of nivolumab on day 1, 1000 mg/m2 of gemcitabine on days 1 and 8, and 70 mg/m2 of cisplatin on day 1 every 3 weeks for up to 6 cycles. Three weeks after completing therapy in the combination phase patients in the investigational arm entered the monotherapy phase to receive 480 mg of nivolumab every 4 weeks until disease progression, unacceptable toxicity, withdrawal, or reached 24 months of treatment. Patients in the gemcitabine and cisplatin arm were treated with 1000 mg/m2 of gemcitabine on days 1 and 8 plus 70 mg/m2 of cisplatin on day 1 every 3 weeks for up to 6 cycles.

The primary end points of the study included OS and PFS per blinded independent central review (BICR). Secondary end points were OS and PFS by PD-L1 positivity (≥1%) and health-related quality of life; exploratory end points were objective response rate (ORR) per BICR and safety.

In the overall Asian subpopulation, the median age was 64.5 years (range, 32-78) and 65.0 years (range, 42-78) in the nivolumab plus gemcitabine and cisplatin and gemcitabine plus cisplatin alone arms, respectively. In both arms, respectively, the majority were male (75.0%; 82.0%) and the majority had an ECOG performance status of 0 (69.4%; 62.3%). Tumor origins at initial diagnosis included bladder cancer (70.8%; 62.3%) and UTUC (27.8%; 36.1%). Patients had a tumor PD-L1 expression of at least 1% (36.1%; 26.2%) or less than 1% (63.9%; 73.8%). Liver metastases were present in 15.3% and 16.4% of patients in the investigational and control arms, respectively.

Additional Efficacy and Safety Data

Findings also demonstrated that evaluable patients with bladder cancer (combination, n = 51; gemcitabine/cisplatin, n = 38) experienced 25 and 20 OS events in the respective arms. Patients with this disease type had a median OS of 23.9 months (95% CI, 18.6-27.5) and 21.7 months (95% CI, 9.7-29.5) with the investigational and control regimens, respectively (HR, 0.77; 95% CI, 0.43-1.40). Those with UTUC (combination, n = 20; gemcitabine/cisplatin, n = 22) experienced 10 vs 14 OS events in the respective arms. The median OS among these respective patients was 28.9 months (95% CI, 14.8-42.2) vs 15.3 months (95% CI, 12.0-23.6; HR, 0.66; 95% CI, 0.29-1.53).

Regarding PFS, patients with bladder cancer experienced 31 and 22 events in the combination vs gemcitabine and cisplatin arms, with a median PFS of 9.5 months (95% CI, 6.2-11.6) vs 6.0 months (95% CI, 3.9-7.4; HR, 0.55; 95% CI, 0.31-0.96). Those with UTUC experienced 12 and 11 PFS events in the combination vs gemcitabine plus cisplatin arms, with a median PFS of 10.3 months (95% CI, 7.6-not evaluable [NE]) vs 7.8 months (95% CI, 4.4-9.3), respectively (HR, 0.51; 95% CI, 0.22-1.20).

The ORR among those in the combination arm was 58.3% (95% CI, 46.1%-69.8%), 56.9% (95% CI, 42.2%-70.7%), and 65.0% (95% CI, 40.8%-84.6%) for the overall Asian population, bladder cancer, and UTUC cohorts, respectively. In the gemcitabine plus cisplatin arm, the ORR was 39.3% (95% CI, 27.1%-52.7%), 34.2% (95% CI, 19.6%-51.4%), and 50.0% (95% CI, 28.2%-71.8%) in the respective cohorts.

In the Asian population, treatment-related adverse effects (TRAEs) of any grade occurred in 97.2% vs 96.5% in the combination and gemcitabine plus cisplatin arms, respectively; grade 3 or greater TRAEs occurred in 63.9% vs 61.4% of patients. Treatment discontinuations because of TRAEs occurred in 12.5% vs 14.0% of patients; grade 3 or greater TRAEs occurred in 8.3% vs 10.5% of patients. Of note, no grade 5 TRAEs occurred in the Asian population.

TRAEs in the Asian population from the combination arm included decreased levels of white blood cells (grade 1/2, 64%; grade ≥3, 31%), anemia (62%; 18%), decreased levels of neutrophils (58%; 37%), nausea (51%; 0%), decreased levels of platelets (44%; 12%), decreased appetite (32%; 1%), vomiting (28%; 0%), constipation (24%; 0%), rash (17%; 1%), malaise (15%; 0%), decreased levels of lymphocytes (12%; 6%), alopecia (12%; 0%), neutropenia (11%; 7%), hiccups (11%; 0%), increased levels of alanine aminotransferase (10%; 1%), increased levels of blood creatine (10%; 0%), fatigue (10%; 3%), pyrexia (10%; 0%), hypothyroidism (10%; 0%), and increased levels of aspartate aminotransferase (7%; 1%).

In the Asian population treated with gemcitabine/cisplatin alone, TRAEs included decreased levels of white blood cells (grade 1/2, 51%; grade ≥3, 17%), anemia (49%; 17%), decreased levels of neutrophils (54%; 32%), nausea (53%; 0%), decreased levels of platelets (28%; 12%), decreased appetite (23%; 0%), vomiting (23%; 3%), constipation (25%; 2%), rash (2%; 2%), malaise (12%; 0%), decreased levels of lymphocytes (12%; 3%), alopecia (17%; 0%), neutropenia (7%; 3%), hiccups (5%; 0%), increased levels of alanine aminotransferase (10%; 0%), increased levels of blood creatine (10%; 0%), fatigue (3%; 0%), pyrexia (9%; 0%), and increased levels of aspartate aminotransferase (12%; 0%).

“The safety profiles were consistent with the established safety of these agents,” Tomita concluded during the presentation. “Notably, there was some hematological toxicity that was numerically higher with nivolumab [plus gemcitabine/cisplatin] and [gemcitabine/cisplatin alone] in the Asian subpopulation than in the global population.”

Disclosures: Tomita listed serving in an advisory role for Eisai, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical; honoraria/lecture fees from Astellas Pharma, Bristol Myers Squibb, Chugai Pharmaceutical, Merck, MSD, Ono Pharmaceutical, Pfizer, and Takeda; and research funding from Astellas Pharma, AstraZeneca, Chugai Pharmaceutical, Eisai, MSD, Ono Pharmaceutical, Pfizer, and Takeda.

References

1. Tomita Y, Ye D, Fujii A, Takeuchi N. Nivolumab (NIVO) plus gemcitabine-cisplatin (GC) vs GC alone in Asian patients with previously untreated unresectable or metastatic urothelial carcinoma (u/mUC) from CheckMate 901. Ann Oncol. 2024;35(suppl 4): S1508. doi:10.1016/j.annonc.2024.10.290
2. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. Updated March 7, 2024. Accessed January 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-combination-cisplatin-and-gemcitabine-unresectable-or-metastatic-urothelial
3. Soria F, Shariat SF, Lerner SP, et al. Epidemiology, diagnosis, preoperative evaluation and prognostic assessment of upper-tract urothelial carcinoma (UTUC). World J Urol. 2017;35(3):379-387. doi:10.1007/s00345-016-1928-x