Dual Immunotherapy Improves DFS in Resectable Kidney Cancer

SAN FRANCISCO — Adjuvant durvalumab (Imfinzi) and tremelimumab (Imjudo) improved disease-free survival (DFS) in a phase III trial of resectable renal cell carcinoma (RCC), but researchers here said the regimen’s impact on quality of life (QoL) should be taken into consideration.

In the RAMPART trial, 3-year DFS improved from 73% with active monitoring following tumor resection to 81% with the dual immunotherapy regimen (HR 0.65, 95% CI 0.45-0.93, P=0.0094).

A substudy presented here by Sophie Merrick, MBChB, of the University College London, showed no difference between the study arms in terms of overall health and QoL at 15 months, as assessed by the European Organisation for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30). But secondary outcomes did reveal significant changes in QoL domains both at this point and at week 16 that favored active monitoring.

“Evaluating quality of life is essential to understanding the overall impact of treatment,” Merrick said at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium.

At week 16, scores for overall health and QoL (-8.1, P=0.0008) and role functioning (-6.0, P=0.04) were significantly worse for patients assigned to durvalumab plus tremelimumab, with both exceeding clinically meaningful thresholds. The dual immunotherapy was also associated with worse fatigue (8.4, P=0.002) and insomnia (8.9, P=0.02), with higher scores here representing worse outcomes.

“By month 15, those early differences appeared to improve, but we saw some late emerging effects in cognitive function … that exceeded clinically meaningful thresholds,” added Merrick. Cognitive function scores at month 15 were 5.8 points lower in the durvalumab-tremelimumab group (P=0.04) while pain scores were 8.8 points higher (P=0.02).

“These findings should be considered alongside the DFS benefit when interpreting the trial results,” she said.

ASCO discussant Kathryn Beckermann, MD, PhD, of Tennessee Oncology and the Vanderbilt University School of Medicine in Nashville, said the findings are “very impactful for how I think about counseling patients.” She noted that discussions with patients regarding the balance between treatment efficacy and QoL are “often the longest and hardest conversations that we have.”

She called it “eye opening” that cognitive function and pain were worse at month 15. “This was after the completion of treatment,” she observed, adding that these longer-term effects on QoL should be included in counseling about potential treatment side effects.

The combination of the PD-L1 inhibitor durvalumab and CTLA-4 inhibitor tremelimumab is not approved in RCC, but the dual immunotherapy regimen carries indication in liver cancer and lung cancer.

The multinational phase III RAMPART trial assigned 790 patients with surgically resected RCC at intermediate or high risk of relapse in a 3:2:2 ratio to either active monitoring (n=340), monotherapy with durvalumab for a year (n=225), or the combination of durvalumab for a year plus tremelimumab at day 1 and week 4 (n=225).

Primary DFS results comparing the durvalumab-tremelimumab and active monitoring arms of the study were first reported last year at the European Society for Medical Oncology annual congress.

At the ASCO Genitourinary Cancers Symposium, Merrick presented a QoL substudy of RAMPART involving 254 patients in English-speaking countries who voluntarily completed the EORTC-QLQ-C30 at baseline and at least one follow-up questionnaire — including 150 from the active monitoring arm and 104 from the durvalumab-tremelimumab arm.

QoL outcomes assessed included changes in overall health and QoL from baseline to month 15 (primary outcome) and at week 16 (secondary outcome). Other secondary outcomes included changes in functional and symptom domains and financial difficulties.

Regarding safety, adverse events (AEs) of any cause occurred in 97% of patients on the dual immunotherapy and 63% of those on active monitoring.

Grade ≥3 AEs of any cause were reported in 40% of patients on the durvalumab-tremelimumab arm compared with 8% on the active monitoring arm, with 32% of patients on the combination discontinuing treatment due to adverse events. Serious AEs occurred in 34% and 6%, respectively.