Metastatic Urothelial Carcinoma

Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma

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BACKGROUND: IMvigor130 demonstrated statistically significant investigator-assessed progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial carcinoma. Overall survival was not improved in interim analyses. Here we report the final overall analysis for group A versus group C.

METHODS: In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged =18 years) with previously untreated locally advanced or metastatic urothelial cancer and who had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), with a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin risk factor score, and investigator’s choice of platinum-based chemotherapy, to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo (ie, group A and group C) and atezolizumab monotherapy (group B) was open label. For groups A and C, all patients received gemcitabine (1000 mg/m2 intravenously; day 1 and day 8 of each 21-day cycle), plus investigator’s choice of carboplatin (area under curve 4·5 mg/mL per min or 5 mg/mL per min; intravenously) or cisplatin (70 mg/m2 intravenously), plus either atezolizumab (1200 mg intravenously) or placebo on day 1 of each cycle. Co-primary endpoints of the study were investigator-assessed progression-free survival and overall survival for group A versus group C in the intention-to-treat (ITT) population (ie, all randomised patients), and overall survival for group B versus group C, tested hierarchically. Final overall survival and updated safety outcomes (safety population; all patients who received any amount of any study treatment component) for group A versus group C are reported here. The final prespecified boundary for significance of the overall survival analysis was one-sided p=0·021. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting.

FINDINGS: Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 851 were assigned to group A (n=451) and group C (n=400). 338 (75%) patients in group A and 298 (75%) in group C were male, 113 (25%) in group A and 102 (25%) in group C were female, and 346 (77%) in group A and 304 (76%) in group C were White. At data cutoff (Aug 31, 2022), after a median follow up of 13·4 months (IQR 6·2-30·8), median overall survival was 16·1 months (95% CI 14·2-18·8; 336 deaths) in group A versus 13·4 months (12·0-15·3; 310 deaths) in group C (stratified hazard ratio 0·85 [95% CI 0·73-1·00]; one-sided p=0·023). The most common grade 3-4 treatment-related adverse events were anaemia (168 [37%] of 454 patients who received atezolizumab plus chemotherapy vs 133 [34%] of 389 who received placebo plus chemotherapy), neutropenia (167 [37%] vs 115 [30%]), decreased neutrophil count (98 [22%] vs 95 [24%]), thrombocytopenia (95 [21%] vs 70 [18%]), and decreased platelet count (92 [20%] vs 92 [24%]). Serious adverse events occurred in 243 (54%) patients who received atezolizumab plus chemotherapy and 196 (50%) patients who received placebo plus chemotherapy. Treatment-related deaths occurred in nine (2%; acute kidney injury, dyspnoea, hepatic failure, hepatitis, neutropenia, pneumonitis, respiratory failure, sepsis, and thrombocytopenia [n=1 each]) patients who received atezolizumab plus chemotherapy and four (1%; unexplained death, diarrhoea, febrile neutropenia, and toxic hepatitis [n=1 each]) who received placebo plus chemotherapy.

INTERPRETATION: Progression-free survival benefit with first-line combination of atezolizumab plus platinum-based chemotherapy did not translate into a significant improvement in overall survival in the ITT population of IMvigor130. Further research is needed to understand which patients might benefit from first-line combination treatment. No new safety signals were observed.

Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial

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Abstract

Background: Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen.

Methods: In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov, number NCT02387996, and is completed. Follow-up is still ongoing.

Findings: Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96-8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0-24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9-39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5-32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5-23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3-4 treatment-related adverse events occurred in 48 (18%) of 270 patients-most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure).

Interpretation: Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma.

Funding: Bristol-Myers Squibb.

Metastatic Urothelial Carcinoma: Cabozantinib and Nivolumab Show Durable Activity

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Cabozantinib may be an ideal primer and a natural combination for enhancing efficacy of immune-checkpoint blockade

A combination of cabozantinib and nivolumab with and without ipilimumab shows durable anti-tumor activity in metastatic urothelial carcinoma and rare genitourinary malignancies, with manageable toxicity.

Immune checkpoint inhibitors, in the form of monoclonal antibodies against CTLA-4, PD-1, and PD-L1, have dramatically changed the treatment approach in several advanced cancers: “Five different PD-1/PD-L1 inhibitors have been approved for patients with platinum-pretreated metastatic urothelial carcinoma, and these agents have become the most promising approach for these patients,” Rosa Nadal, MD, PhD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland, told MedPage Today. “However, only 20-25% of patients respond to these agents in monotherapy. This modest activity has researchers investigating combination therapy to improve response rates, and benefit more patients.”

For example, the CheckMate-032 study, evaluated nivolumab in combination with ipilimumab and found that this combination has superior clinical activity in a similar patient population. Additionally, translational work performed at the NCI demonstrated that cabozantinib has immunomodulatory properties that appear to counteract tumor-induced immunosuppression.

Cabozantinib can reduce the percentage of CD4-positive T-regulatory cells (immunosuppressive cells) by acting on T-cell polarization via inhibition of transcription factor Foxp3. Another observation was that patients with metastatic urothelial cancer with a lower percentage of CD4 T-regulatory cells at baseline have a better response than those with a higher percentage at baseline. These observations provided the rationale for combining cabozantinib with immunotherapy, Nadal continued.

“We have learned that cabozantinib itself modulates the immune system, in addition to its dual inhibitory effect on MET and VEGFR2. Therefore, cabozantinib may be an ideal primer and a natural combination for enhancing efficacy of immune-checkpoint blockade.”

At the most recent European Society for Medical Oncology congress, she presented the final results of a phase I cohort study led by Andrea Apolo, MD, head of the NCI’s Bladder Cancer Section, designed to determine the dose-limiting toxicity and a recommended phase II dose for the combination of cabozantinib and nivolumab and the combination of cabozantinib, nivolumab, and ipilimumab.

The study included 42 patients with a metastatic genitourinary cancer, with disease progression on at least one standard therapy except for patients with rare histologies with no standard-of-care therapy who could participate in the first-line setting. Fifteen patients had urothelial carcinoma of the bladder, and 27 had non-urothelial carcinoma genitourinary malignancies. Two-thirds of patients had two or more prior systemic regimens; more than half of the patients had visceral disease (liver and/or lung metastases).

 This dose-escalation cohort included four dose levels of cabozantinib and nivolumab and three of cabozantinib, nivolumab, and ipilimumab.

Of the 42 patients, 24 received the doublet therapy and 18 had the triplet therapy. The overall response rate in the overall population was 33%. After 16 months of follow-up, the median duration of response has not been reached, the team reported. Most patients who responded had ongoing responses at the time of the response analysis. “Two-thirds of responders to cabozantinib plus nivolumab are ongoing, as are three-quarters of responders to cabozantinib, nivolumab, and ipilimumab. Response duration is likely to extend well beyond 1 year in some of the patients,” said Nadal.

Among patients with urothelial carcinoma, 38% responded. One of the four urachal adenocarcinoma patients (25%) responded, as did both of the patients with squamous cell carcinoma of the bladder, one of nine prostate cancer patients (11%), and both of the sarcomatoid renal cell carcinoma and half of the penile cancer patients (50%).

“We were delighted to see responses in patients with rare genitourinary tumors,” said Nadal. “Some of these tumors do not have any established standard-of-care treatment, and cabozantinib in combination with immune-checkpoint inhibitors benefits them.”

Median progression-free survival was 5.9 months, and median overall survival was 20 months.

 The most common toxicities, which were mostly mild, she said, were fatigue (71%), nausea/vomiting (71%), diarrhea (67%), skin disorders (67%), anorexia (62%), and oral mucositis or sore throat (62%). About 70% of patients developed grade 3 or 4 toxicities, most of which were attributable to class-based side effects of VEGF inhibitors. This is comparable to that seen among patients who receive cabozantinib monotherapy, she noted.

The most common potential immune-related adverse event was pneumonitis, experienced by 11% of patients receiving cabozantinib, nivolumab, and ipilimumab.

There is an added risk for liver toxicities, particularly with triplet therapy, Nadal cautioned. However, these were mostly low-grade toxicities and were manageable by holding drugs and/or dose-reducing cabozantinib. One patient developed immune-related hepatitis and required treatment with corticosteroids. The side-effect profile remains acceptable, she added.

“Both cabozantinib-nivolumab and cabozantinib-nivolumab-ipilimumab are safe and well tolerated, albeit with low-grade clinical and laboratory adverse events compared with either single agent.”

The recommended phase II dose is cabozantinib at 40 mg plus nivolumab at 3 mg/kg and cabozantinib at 40 mg plus nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg.

Nadal noted that additional expansion cohorts of metastatic urothelial carcinoma, renal cell carcinoma and rare genitourinary tumors are ongoing within the same study. Based on the safety data, a three-arm randomized phase III study of cabozantinib-nivolumab versus cabozantinib-nivolumab-ipilimumab versus sunitinib (standard-of-care arm) has started enrollment in renal cell carcinoma. Additional large multicenter trials of the triplet combination in rare tumors and a randomized trial of the triplet combination in bladder cancer are in development.

“Our results demonstrated acceptable safety and promising antitumor activity for cabozantinib and nivolumab with or without ipilimumab in patients with metastatic urothelial carcinoma,” Nadal summed up. “The results also showed robust antitumor activity in patients with rare genitourinary malignancies when many treatment options aren’t available. We’re waiting for definitive efficacy from ongoing clinical trials.”