Benjamin Saylor

The co-primary end points of overall survival in patients with metastatic urothelial cancer (UC) were not met in the phase 3 DANUBE trial of durvalumab in combination with tremelimumab and durvalumab (Imfinzi) monotherapy, according to results presented at the 2020 ESMO Virtual Congress.

Neither monotherapy with durvalumab (Imfinzi) or combination treatment with durvalumab plus tremelimumab met co-primary end points of overall survival versus chemotherapy for the treatment of metastatic urothelial cancer (UC).

However, secondary analyses suggested that tremelimumab bolstered the anti-tumor activity of durvalumab, particularly in patients whose tumors had high PD-L1 expression.

In introducing the DANUBE study, investigator Thomas Powles, MBBS, MRCP, MD, explained that although platinum-based chemotherapy yields initial high responses as first-line treatment for metastatic urothelial cancer, “patients relapse, and long-term, durable remissions are rare.

“Both atezolizumab [Tecentriq] and pembrolizumab [Keytruda] are approved in the cisplatin-ineligible, PD-L1-positive population in this frontline space. Their approval is based off 2 single-arm trials with relatively modest numbers.

 We don't currently have any mature, randomized overall survival data in this setting,” added Powles, professor of genitourinary oncology, director of Barts Cancer Centre, Queen Mary University of London, United Kingdom.

Durvalumab is approved by the FDA for the treatment of platinum-refractory, metastatic UC. Previous research has indicated that tremelimumab alone and the combination of durvalumab plus tremelimumab shows activity in platinum-refractory, metastatic UC regardless of PD-L1 expression.

The DANUBE trial evaluated durvalumab, with or without tremelimumab, vs platinum-based chemotherapy, as first-line treatment for metastatic UC (NCT02516241). The study included 1032 patients with untreated, unresectable, locally advanced, or metastatic UC.

Patients were randomized 1:1:1 to receive 1500 mg durvalumab IV once monthly until progression (n = 346); 1500 mg durvalumab IV once monthly until progression plus 75 mg tremelimumab once monthly for up to 4 doses (n = 342); and a standard-of-care chemotherapy regimen of gemcitabine plus cisplatin or carboplatin up to 6 cycles (n = 344). Randomization was stratified by cisplatin eligibility, PD-L1 status (high or low), and presence or absence of liver and/or lung metastases.

Baseline characteristics such as age, region, and pure transitional cell carcinoma were generally well balanced among the treatment groups.

Co-primary end points consisted of overall survival (OS) for durvaluamb vs chemotherapy in patients with high PD-L1 expression and OS for durvalumab plus tremelimumab vs chemotherapy in the intention-to-treat (ITT) population.

The minimum follow-up time was 34 months, and median follow-up for survival was 41.2 months for all patients.

Median OS for patients in the durvalumab-only group was 14.4 months vs 12.1 months for the chemotherapy group (HR, 0.89; 95% CI, 0.71-1.11) In the durvalumab plus tremelimumab cohort. Median OS was 15.1 months vs 12.1 months for the chemotherapy group (HR, 0.85; 95% CI, 0.72-1.02).

In regards to anti-tumor activity, median duration of response in the ITT population for patients in the durvalumab-only, durvalumab plus tremelimumab, and chemotherapy groups was 9.3 months (95% CI, 5.8-20.5), 11.1 months (95% CI, 7.9-18.5), and 5.7 months (95% CI, 5.6-6.2), respectively.

Median duration of response in the PD-L1-high population in the durvalumab only, durvalumab plus tremelimumab, and chemotherapy groups was 18.5 months (95% CI, 7.6-not estimable), 10.0 months (95% CI, 7.4-18.7), and 5.8 months (95% CI, 5.1-7.0), respectively.

Treatment-related adverse events occurred in 56% of the durvalumab cohort, 75% of the durvalumab plus tremelimumab cohort, and 90% of the chemotherapy cohort. Both durvalumab monotherapy and durvalumab/tremelimumab had manageable safety profiles, and no new safety signals were observed.

Reflecting on the results, Powles commented, “Overall, with a median survival 41 months, this DANUBE data has 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.”

He added, “While the trial was negative, it does give us some provocative data…for future trials."

1. Powles TB, van der Heijden MS, Gauna Castellano D, et al. A phase III, randomized, open-label study of first-line durvalumab (D) with or without tremelimumab (T) vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE). Paper presented at: European Society of Medical Oncology virtual congress; September 19-21, 2020. Abstract 697O.

2. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. 

. 2017;18(11):1483-1492. doi:10.1016/S1470-2045(17)30616-2

3. Balar AV, Galsky MD, Rosenberg JE, IMvigor 210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. 

. 2017; 389(10064)67-76. doi: 10.1016/S0140-6736(16)32455-2

4. Sharma P, Sohn J, Shin SJ, et al. Efficacy and tolerability of tremelimumab in locally advanced or metastatic urothelial carcinoma patients who have failed first-line platinum-based chemotherapy. 

. 2020;26-61-70. doi:10.1158/1078-0432.CCR-19-1635

5. Balar AV, Mahipal A, Grande E, et al. Durvalumab + tremelimumab in patients with metastatic urothelial cancer. Paper presented at: 2018 American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago, IL.

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The co-primary end points of overall survival in patients with metastatic urothelial cancer were not met in the phase 3 DANUBE trial of durvalumab in combination with tremelimumab and durvalumab monotherapy, according to results presented at the 2020 ESMO Virtual Congress.

Durvalumab With or Without Tremelimumab Fails to Meet OS Endpoints in Urothelial Cancer

At 4 years of follow-up, nivolumab (Opdivo) and ipilimumab (Yervoy) in combination as first-line therapy of advanced renal cell carcinoma (RCC) demonstrated durable benefit versus sunitinib (Sutent), according to research presented at the 2020 ESMO Virtual Congress.

Investigators also reported that a subgroup of patients with 1 or more target kidney lesions experienced kidney tumor reduction and other benefits from the combination treatment.

“Nivolumab plus ipilimumab was the first immunotherapy combination to demonstrate an overall survival advantage over sunitinib in intermediate- and poor-risk patients with advanced renal cell carcinoma,” CheckMate-214 investigator Laurence Albiges, MD, PhD, said in a press release.

 “Now, after 4 years, the durable efficacy seen in CheckMate-214 represents important progress towards the aim of changing survival expectations for these patients,” added Albiges, Head of Genitourinary Unit, Gustave Roussy Institute, Villejuif, France.

The randomized, open-label phase 3 CheckMate-214 trial evaluated the combination of nivolumab and ipilimumab versus sunitinib in patients with previously untreated advanced or metastatic RCC.

Patients in the combination group (n = 550) received 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg nivolumab every 2 weeks. Patients in the sunitinib group (n = 546) received 50 mg once daily for 4 weeks, followed by 2 weeks off before continuation of treatment. Treatment was given until progression or unacceptable toxic effects.

Primary end points included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in an intermediate- to poor-risk patient population. In addition, non-prespecified, post hoc exploratory efficacy analyses were performed in a subgroup of study patients who had not undergone prior nephrectomy and who had 1 or more target kidney lesions.

In intermediate- to poor-risk patients treated with nivolumab/ipilimumab, median OS was 48.1 months, compared with 26.6 months in patients who received sunitinib (HR, 0.65; 95% CI, 0.54-0.78). The 4-year OS rate for the combination treatment and sunitinib groups was 50.0% and 35.8%, respectively. ORR was also higher in patients receiving combination treatment versus sunitinib, with more ongoing responses in intermediate- to poor-risk patients (65% vs 50%, respectively). Median duration of response was not reached in the combination treatment arm and was 19.7 months for sunitinib.

Analysis of patients in the intention-to-treat (ITT) population with 48 months’ follow-up also pointed to the benefits of nivolumab/ipilimumab treatment. Median OS was not reached for all patients in the combination treatment group vs 38.4 months in the sunitinib group (HR, 0.69; 95% CI, 0.59-0.81), with 4-year OS rates of 53.4% and 43.3%, respectively. ORR was higher in patients receiving nivolumab/ipilimumab, with more ongoing responses compared to patients receiving sunitinib (65% vs 52%). Median duration of response was not reached in patients treated with nivolumab/ipilimumab and was 23.7 months in the sunitinib group.

In the subgroup of patients with 1 or more target kidney lesions, ORR was 34% in the nivolumab/ipilimumab group vs 15% in the sunitinib group. A 30% or greater reduction in target kidney lesion(s) was observed in 35% of patients receiving the combination treatment vs 20% in patients receiving sunitinib.

Treatment-related adverse events of any grade occurred in 94% of patients receiving combination treatment and 97.0% of patients receiving sunitinib, and no new safety signals emerged over the longer follow-up.

“We have now evaluated Opdivo plus Yervoy in multi-year phase 3 trials across RCC, melanoma, non-small cell lung cancer, and mesothelioma, and in all of these studies, we have seen improved survival compared to the existing standard of care,” said Nick Botwood, MD, vice president, interim head, Oncology Development, Bristol Myers Squibb, in a press release. “The 4-year results from CheckMate -214 build on our understanding of and leadership in addressing advanced RCC, reinforcing the potential for durable, long-term survival benefits with Opdivo plus Yervoy in the first-line setting. Taken as a whole, these data provide further evidence for the value of distinct but complementary dual checkpoint inhibition in the treatment of advanced cancers.”

1. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma 711P in CheckMate 214: 4-year follow-up and subgroup analysis of patients without nephrectomy. Presented at: European Society of Medical Oncology virtual congress; September 19-21, 2020. Abstract 711P.

2. Bristol Myers Squibb. Four-year data continue to show superior, long-term survival benefit with Opdivo (nivolumab) plus Yervoy (ipilimumab) in patients with previously untreated advanced or metastatic renal cell carcinoma. Press release. September 17, 2020. Accessed September 18, 2020. https://bit.ly/3mCwhwO.

At 4 years of follow-up, nivolumab and ipilimumab in combination as first-line therapy of advanced renal cell carcinoma demonstrated durable benefit versus sunitinib, according to research presented at the 2020 ESMO Virtual Congress.

Benjamin Saylor | Authors

Articles

Durvalumab With or Without Tremelimumab Fails to Meet OS Endpoints in Urothelial Cancer

Durable Benefit Observed at 4 Years With Nivolumab Plus Ipilimumab in Advanced RCC