Compared with chemotherapy alone, patients with unresectable or metastatic urothelial carcinoma derived a greater survival benefit with Opdivo (nivolumab) plus frontline chemotherapy with gemcitabine and cisplatin, followed by Opdivo maintenance therapy, recent trial findings demonstrated.
According to data from the phase 3 CheckMate 901 trial presented at the 2023 ESMO Congress, adding Opdivo to frontline chemotherapy statistically improved overall survival (OS; the time from the start of treatment when a patient with cancer is still alive) and progression-free survival (PFS; the time during and after treatment when a patient with cancer is alive without disease worsening).
“(Opdivo) plus gemcitabine is the first frontline concurrent checkpoint inhibitor plus chemotherapy combination to improve OS in this setting, with results supporting (Opdivo) plus cisplatin-based chemotherapy as a new standard of care for patients with unresectable or metastatic urothelial cancer,” Dr. Michiel S. Van der Heijden, Netherlands Cancer Institute, Amsterdam, the Netherlands, said during a presentation of the data.
OS and PFS in CheckMate 901
Median OS with Opdivo plus chemotherapy was 21.7 months, compared with 18.9 months with chemotherapy alone, reducing the risk of death by 22%, meeting the primary end point of the study (meaning that this outcome aligned with what the researchers wanted to accomplish with the trial). The 12- and 24-month OS rates with the Opdivo combination were 70.2% and 46.9%, versus 62.7% and 40.7%, respectively, with chemotherapy alone.
OS benefit with the addition of Opdivo was also seen across the subgroup analysis, including age, sex, race, region, ECOG performance status (which measures a patient’s level of functioning), PD-L1 expression, liver metastases and previous systemic anticancer therapy.
PFS was also met in the trial, with a median PFS of 7.9 months with Opdivo plus chemotherapy, compared with 7.6 months with chemotherapy alone, reducing the risk for progression by 28%. The 12- and 24- months PFS rates with the addition of Opdivo were 34.2% and 23.5%, compared with 21.8% and 9.6%, respectively, in the chemotherapy-alone arm.
He noted that, for the primary analysis of PFS, patients who went on to receive subsequent anticancer therapy before disease progression were censored (Opdivo combination arm, 8% versus chemotherapy-alone arm, 24%). Immunotherapies were the most commonly used in the chemotherapy-alone arm. Therefore, since this may have impacted the primary analysis, the investigators conducted a sensitivity analysis and uncensored this patient population, finding that the median PFS with Opdivo plus chemotherapy was 7.9 months, compared with 7.5 months in the chemotherapy-alone arm.
The objective response rate (ORR; the percentage of patients with a partial or complete response to treatment) in the Opdivo combination arm was 57.6%, including a complete response (CR; the disappearance of all signs of cancer from treatment) rate of 21.7%, partial response (PR; decrease in tumor size from treatment) rate of 35.9%, stable disease (SD; cancer that has neither increased or decreased in severity) rate of 25.3%, and progressive disease (PD; cancer that is spreading, growing or getting worse) rate of 7.6%. The ORR in the chemotherapy-alone arm was 43.1%, including a CR rate of 11.8%, PR rate of 31.3%, SD rate of 28.3%, and PD rate of 15.8%.
When evaluating any objective response, median time to response (TTR) with Opdivo plus chemotherapy was 2.1 months versus 2.1 months with chemotherapy alone, while median duration of response (DOR; the time from when a patient response to therapy until disease progression or death) was 9.5 months and 7.3 months, respectively. Among those who experience a CR, median TTR was 2.1 months in both arms and median DOR was 37.1 months and 13.2 months.
Median DOR with the addition of Opdivo was 9.5 months, compared with 7.3 months with chemotherapy alone. The 12- and 24-month DOR rates with Opdivo combination therapy were 46.2% and 35%, compared with 29.2% and 12.6%, respectively, with chemotherapy alone.
“Complete responses were also achieved rapidly, and median duration of complete remission had a notable, substantial improvement in duration over (chemotherapy) alone, indicating that Opdivo plus (chemotherapy) is associated with rapid, deep and durable responses,” Van der Heijden highlighted.
More patients in the chemotherapy-alone arm went on to receive subsequent immunotherapy (60 versus eight), compared with the Opdivo arm. Van der Heijden noted that the proportion of patients receiving non-immunotherapy subsequent therapy, including surgery, radiotherapy and/or platinum-based chemotherapy, was similar in both arms.
Any-grade treatment-related side effects occurred in 97% of the Opdivo combination arm, compared with 93% of the chemotherapy-alone arm, with 62% and 52%, respectively, being severe or worse. The most common severe or worse treatment-related side effects in the Opdivo combination and chemotherapy-alone arms included anemia (22% versus 18%, respectively), neutropenia (19% versus 15%; lower than normal number of white blood cells called neutrophils), decreased neutrophil count (14% versus 11%; this may impact how a patient’s immune system fights off infections), decreased platelet count (8% versus 5%), decreased white blood cell count (10% versus 4%), thrombocytopenia (7% versus 5%; lower than normal number of platelets in the blood) and leukopenia (2% each; lower than normal number of white blood cells called leukocytes).
Lastly, health-related quality of life was stable in both arms on the study.
The median duration of study therapy was 7.4 months in the Opdivo combination arm, compared with 3.7 months with chemotherapy alone. In total, 74% of patients treated with Opdivo and 55% of those treated with chemotherapy alone completed six cycles of treatment per the study protocol. Treatment discontinuation occurred as a result of disease progression (7% versus 17%, respectively) and study drug toxicity (8% each).
Of those treated with Opdivo plus chemotherapy in the combination phase, 244 went on to receive Opdivo monotherapy maintenance therapy, with 20 (8%) completing treatment and 23 (9%) still on therapy at data cutoff.
Addressing an Unmet Need
“For decades, cisplatin-based chemotherapy is the first-line standard of care for eligible patients with advanced urothelial cancer in first the line. No new agents have improved OS when added concurrently to chemotherapy in the first-line treatment of advanced urothelial cancer,” Van der Heijden explained, however, adding that Bavencio (avelumab) has been approved in a maintenance setting for this patient population who have not progressed on or immediately after first-line platinum-based chemotherapy.
“Still an unmet need remains in first-line setting for treatments that improve patient outcomes,” he added.
Therefore, in this phase 3 trial, patients were randomized to receive either Opdivo plus chemotherapy with gemcitabine and cisplatin every three weeks for up to six cycles (304 patients) or the gemcitabine/cisplatin regimen alone (304 patients). Patients treated with Opdivo in the combination phase then went on to receive Opdivo every four weeks until disease progression, unacceptable toxicity, withdrawal or up to a maximum of 24 months of maintenance therapy.
OS and PFS served as the primary end points, while the secondary end points included OS and PFS by PD-L1 of 1% or greater and health-related quality of life. The key exploratory end points were ORR and safety.
Patients were eligible for the trial if they were 18 years of age or older; had previously untreated, unresectable or metastatic urothelial carcinoma involving the renal pelvis, ureter, bladder or urethra; were cisplatin eligible; and had an ECOG performance status of 0 to 1.
Median follow-up was 33.6 months.
At baseline, patients in the Opdivo arm were a median age of 65 years (range, 32-86), while the majority were male (78%), White (69%), and had an ECOG performance status of 0 (53%). At initial diagnosis, 77% of patients had urinary bladder disease, 11% had renal pelvis disease, and 12% with other. In total, 37% of patients in this arm had PD-L1 expression of 1% or more versus 63% with less than 1%. Lastly, 21% of patients had liver metastases.
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