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Checkpoint Inhibitor and Chemotherapy Combinations Fail to Move Bar as First-Line Therapy for Advanced Urothelial Cancer


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Two different phase III studies found that combining an anti–PD-1/PD-L1 checkpoint inhibitor (pembrolizumab in KEYNOTE-361) with platinum-based chemotherapy or with another checkpoint inhibitor (the anti–CTLA-4 antibody tremelimumab in DANUBE) failed to significantly improve overall or progression-free survival over standard-of-care chemotherapy alone in first-line therapy of platinum-eligible patients with advanced or metastatic urothelial cancer. The results of the KEYNOTE-361 and DANUBE trials were presented at the European Society for Medical Oncology Virtual Congress 2020.1,2

The current standard of care in the first-line treatment of patients with metastatic urothelial cancer is platinum-based chemotherapy. Checkpoint inhibitors have already been approved for second-line therapy in this disease and in cisplatin-ineligible patients whose tumors express PD-L1. Moreover, Avelumab is recommended as switch maintenance therapy for patients who do not experience disease progression on first-line chemotherapy, and both pembrolizumab and atezolizumab are recommended as first-line monotherapies for patients with PD-L1–expressing tumors who are ineligible for platinum-based chemotherapy regardless of PD-L1 status.

KEYNOTE-361: Study Design

KEYNOTE-361 randomly assigned 1,010 patients with locally advanced unresectable or metastatic urothelial cancer and ECOG performance status of 0, 1, or 2 from 201 sites in 21 countries in a 1:1:1 ratio to receive either pembrolizumab plus gemcitabine and cisplatin or carboplatin vs pembrolizumab alone vs the same chemotherapy regimen alone. Pembrolizumab was given for up to 2 years and chemotherapy, for up to 6 cycles. Patients were stratified for tumor PD-L1 expression (combined positive score [CPS] ≥10 vs CPS < 10) and by choice of platinum agent. Treatment was continued until disease progression or intolerable toxicity. At the end of the day, due to the statistical design, the investigators were unable to compare the pembrolizumab monotherapy arm vs chemotherapy alone.

At ESMO 2020, Ajjai Alva, MD, of the University of Michigan, Ann Arbor, presented the results comparing the pembrolizumab plus chemotherapy arm vs the chemotherapy-alone arm for the co-primary endpoints—progression-free survival and overall survival as assessed by blinded independent central review. The median time from randomization to data cutoff was 31 months. The key characteristics were well balanced across the three study arms. Approximately 22% had liver metastasis, and 55% were chosen for carboplatin per treating investigator choice.

KEYNOTE-361: Survival Outcomes and Toxicity

The results for the co-primary endpoints of progression-free survival and overall survival failed to show a statistically significant benefit of the combination therapy over chemotherapy alone. Median progression-free survival by blinded independent central review was 8.3 months with the combination vs 7.1 months with chemotherapy alone. Similar results were seen with investigator-assessed progression-free survival in an exploratory analysis.

“The two curves for [progression-free survival] overlap early but separate out a bit later on, suggesting some durable remissions on the combination,” Dr. Alva stated.

The results were similar for overall survival, with no significant differences between the treatment arms. “No subgroup really stood out for a benefit in overall survival from the combination therapy,” he stated. “Exploratory analyses accounting for subsequent anti–PD-1/PD-L1 therapy, which occurred in 45% of the control chemotherapy arm subjects, did not show a significant difference between treatment arms,” Dr. Alva noted.

“The objective response rate was 55% for the combination arm, about 10% higher than chemotherapy alone. It was 33% for the pembrolizumab arm, which signals that cytotoxic chemotherapy perhaps does a better job in initial disease control,” he continued.

“Cytotoxic chemotherapy controls the disease early on more often than immunotherapy alone.”
— Ajjai Alva, MD

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As would be expected, the durability of response for responding patients was much longer with pembrolizumab monotherapy—28 months—than with chemotherapy alone—6.2 months.

Overall, pembrolizumab did not add appreciable adverse effects to the safety profile of chemotherapy alone. “Pembrolizumab was extremely well tolerated as monotherapy,” Dr. Alva added.

Treatment-related adverse events grades 3 to 5 were reported in 75% with the combination, 16.9% with pembrolizumab only, and 71.6% with chemotherapy alone. Discontinuation rates due to an adverse event were 30.9%, 15.9%, and 18.1%, respectively.

“Another disappointment of this trial is that the biomarker [ie, PD-L1] did not perform as well as we had hoped for. We need to explore additional biomarkers in immunotherapy,” he told listeners.

DANUBE Trial

In the phase III DANUBE trial, neither monotherapy with durvalumab or combination treatment with durvalumab plus tremelimumab significantly improved overall survival—the primary endpoint—vs chemotherapy for metastatic urothelial cancer. When secondary analyses dug deeper into the data, it appeared that tremelimumab bolstered the antitumor activity of durvalumab, particularly in patients whose tumors had high PD-L1 expression.

“Although most patients with metastatic urothelial cancer will respond to first-line platinum-based chemotherapy, patients relapse and, long-term, durable remissions are rare. Both atezolizumab and pembrolizumab are approved in the cisplatin-ineligible, PD-L1–positive population in this front-line space. Their approval is based on two single-arm trials with relatively modest numbers. We don’t currently have any mature, randomized overall survival data in this setting,” explained lead study author Thomas Powles, MD, PhD, Professor of Genitourinary Oncology and Director of Barts Cancer Centre, Queen Mary University of London.

Thomas Powles, MD, PhD

Thomas Powles, MD, PhD

Durvalumab is approved by the U.S. Food and Drug Administration for the treatment of platinum-refractory, metastatic urothelial cancer. Preliminary studies suggested that tremelimumab alone and the combination of durvalumab plus tremelimumab may be active in platinum-refractory, metastatic urothelial cancer regardless of the level of PD-L1 expression.

DANUBE Trial: Study Details

The open-label, randomized, phase III DANUBE trial evaluated durvalumab, with or without tremelimumab, vs platinum-based chemotherapy as first-line treatment of metastatic urothelial cancer. Patients with untreated, unresectable, locally advanced or metastatic urothelial cancer (n = 1,032) were randomly assigned 1:1:1 to receive 1,500 mg of durvalumab intravenously (IV) every month until disease progression (n = 346); 1,500 mg of durvalumab IV once monthly until disease progression plus 75 mg of tremelimumab once a month for up to four doses (n = 342); and a standard-of-care chemotherapy regimen of gemcitabine plus cisplatin or carboplatin for up to six cycles (n = 344). A total of 60% of all patients received cisplatin and 40% received carboplatin. Stratification factors were cisplatin eligibility, PD-L1 status (high or low), and presence or absence of liver and/or lung metastases. Baseline demographic and disease characteristics were generally well balanced among all three treatment groups. Co-primary endpoints consisted of overall survival for durvalumab vs chemotherapy in patients with high PD-L1 expression and in the overall intention-to-treat population.

DANUBE Trial: Survival Outcomes

At a median follow-up of 41.2 months, median overall survival for patients in the durvalumab-alone group was 14.4 months vs 12.1 months for the chemotherapy group. In the durvalumab-plus-tremelimumab cohort, median overall survival was 15.1 months vs 12.1 months for the chemotherapy group.

The median duration of response in the intention-to-treat population for patients in the durvalumab-alone, durvalumab-plus-tremelimumab, and chemotherapy groups was 9.3 months, 11.1 months, and 5.7 months, respectively.

The median duration of response in the PD-L1–high population in the durvalumab-alone, durvalumab-plus-tremelimumab, and chemotherapy groups was 18.5 months, 10.0 months, and 5.8 months, respectively.

KEY POINTS

  • Two large phase III trials failed to show a survival benefit with the combination of checkpoint inhibitor plus standard platinum-based chemotherapy over chemotherapy alone in advanced or metastatic urothelial cancer.
  • Cisplatin-based chemotherapy remains the standard of care for first-line therapy of platinum-eligible patients in this setting.
  • The optimal treatment of platinum-ineligible patients is unclear and warrants further study.

DANUBE Trial: Safety

Treatment-related adverse events were lowest in the durvalumab-alone group (56%) compared with 75% in the durvalumab-plus-tremelimumab group and 90% in the chemotherapy cohort. Both durvalumab monotherapy and durvalumab/tremelimumab had manageable safety profiles, and no new safety signals were observed.

“Overall, with a median survival of 41 months, these DANUBE data have the most robust data set to date. I think it gives a good impression of the role of both monotherapy and the combination in this environment,” Dr. Powles commented. “Although the trial was negative, it does give us some provocative data…for future trials.” 

DISCLOSURE: Dr. Alva has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Merck, and Pfizer; has received institutional research funding from Arcus Biosciences, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Genentech, Harpoon Therapeutics, Janssen, Merck Sharp & Dohme, Mirati Therapeutics, Progenics, Prometheus Laboratories, and Roche; and has been reimbursed for travel, accommodations, or other expenses by Bristol Myers Squibb and Merck. Dr. Powles has received honoraria from AstraZeneca, Bristol Myers Squibb, Ferring, GLG Group, Janssen Research & Development, Merck, Novartis, Pfizer, Roche/Genentech, and Seattle Genetics/Astellas; has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Incyte, Ipsen, Merck, Novartis, Pfizer, and Seattle Genetics; has received research funding from AstraZeneca/MedImmune and Roche/Genentech; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Bristol Myers Squibb, Ferring, MSD, Novartis/Ipsen, Pfizer, Research to Practice, and Roche/Genentech.

REFERENCES

1. Alva A, Csöszi T, Ozguroglu M, et al: Pembrolizumab combined with chemotherapy (C) vs C alone as first-line therapy for advanced urothelial carcinoma: KEYNOTE-361. ESMO Virtual Meeting 2020. Abstract LBA23. Presented September 19, 2020.

2. Powles TB, Van der Heijden MS, Castellano Gauna D, et al: A phase III, randomized, open-label study of first-line durvalumab with or without tremelimumab vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE). ESMO Virtual Congress 2020. Abstract 697O. Presented September 19, 2020.


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