ABSTRACT
Background: Bladder-preserving combinedmodality therapies constitute an alternative to radical cystectomy for selected pts with MIBC. In preclinical studies, combination of radiation and dual checkpoint blockade appears to activate non-redundant immune mechanisms, potentiating antitumor activity. The purpose of the present study is to explore feasibility, toxicity and activity of this approach in MIBC. Methods: Pts with localized MIBC in clinical stages T2-4a N0 M0, ECOG 0-1, without contraindications to immunotherapy, who either wished for bladder preservation or were ineligible for cystectomy, were included in this phase II study. Treatment consisted of initial transurethral resection (TUR) of the tumor, followed by durvalumab 1,500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for 3 doses. Normofractionated external-beam RT was started 2 weeks later, at doses of 46 Gy to minor pelvis and 64-66 Gy to bladder. Pts with either residual or relapsed MIBC were offered salvage cystectomy. The primary endpoint was complete response (CR) defined as absence of MIBC at post-treatment tumor site biopsy. A 2- stage sequential design was used (CR rate P0=5, P1=0.7, α=0.10, β=0.20) requiring at least 6 CR in the first 12 pts to expand to a second cohort of 20 pts. Results: From 1/2019 to 8/2020, 32 pts were enrolled at 6 centers. Median age was 71 years (49-91). PS was 0 in 24 pts,1 in 8. 25 were males. Clinical stage was T2 in 28 pts, T3 in 3 and T4a in 1. All pts received at least two immunotherapy cycles. The median dose of RT administered was 64 Gy (60-65). CR at posttreatment biopsy was documented in 26 (81%) pts, 2 pts had residual MIBC and 4 pts were not evaluated due to rejection (1), clinical impairment (1), death from COVID 19 (1) and a suspected treatment-related death from peritonitis (1). After a median follow up of 6.1 months (2.5 - 20.1), 2 pts underwent salvage cystectomy because of MIBC and T1 relapses, respectively. The estimated 6-months rates for disease-free survival (DFS) with bladder intact, DFS and overall survival were 76% (95%CI, 61%-95%), 80% (95%CI, 66%-98%) and 93% (95%CI, 85%-100%), respectively. A total of 31 (97%) pts experienced adverse events related to RT and/or immunotherapy, with diarrhea (41%) and urinary disorders (37.5%) as the most frequent. Grade 3 or 4 adverse events related to therapy were reported in 31% pts, being the most frequent gastrointestinal toxicity (12.5%), acute kidney failure (6%) and hepatitis (6%). Conclusions: A combined-modality approach including durvalumab + tremelimumab with concurrent RT is feasible and safe, showing high efficacy in terms of response and eliciting bladder preservation in a large number of pts. Further research on this approach as an alternative to cystectomy is warranted.
ABSTRACT
Background: Cancer is recognized as a major risk factor for severe COVID19. However little is known about the impact of oncologic treatments in the evolution of the disease. On the other hand, the influence of SARS-CoV2 in cancer response remains to be established. We aim to determine both aspects in renal cancer patients receiving different therapeutic options. Methods: We designed a retrospective casecontrol study to compare the outcome of patients with advanced renal cancer who developed COVID19 under antiangiogenic treatment (cohort A [ChA]) vs immunotherapy (alone or in combination: cohort B [ChB]) vs matched controls (cohort C [ChC]). Controls were renal cancer patients who were not infected during the period of study. One control per case was selected regarding age, gender, kidney cancer histology and type of treatment. Results: From May 20 to Feb 21, 80 patients were recruited. We present the first 55 patients included (15 ChA, 16 ChB and 20 ChC, 4 patients were screening failure) from 13 centers in Spain. Median age was 62 (range 25 to 88) overall and 62 (range 44 to 88) in Ch A, 64,5 (range 42 to 83) in ChB and 61 (range 41 to 77) in ChC. 38 patients were male and 13 were female. Overall 45 cases were clear cell carcinoma (13 ChA, 14 ChB and 18 ChC), 4 papillary (1 ChA, 2 ChB and 1 ChC), 1 chromophobe (ChA) and 1 unclassified (ChC). Median number of prior lines of treatment was 2 (range 1 to 6) overall, (1 [range 1 to 4] in ChA, 2 [range 1 to 4] in ChB and 2 [range 1 to 6] in ChC). 25 patients required treatment interruptions (8 in ChA [32%], 14 in ChB [56%] and 3 [12%] in ChC). 9 patients were hospitalized (4 in Ch A, 5 in ChB and none in ChC) for a median of 10 days (range 4 to 16) overall (7 [range 4 to 14] in ChA and 12 [range 5 to 16] in ChB). No patient required ICU admission. Best tumor response was complete or partial (CR+PR) in 25 patients (5 [20%] in ChA, 9 [36%] in ChB and 11 [44%] in ChC). Clinical benefit (CR+PR+stable disease) was observed in 38 patients (11 [28,9%] in ChA, 10 [26,3%] in ChB and 17 [44,7%] in ChC). One patient in ChB died (due to COVID19). Updated results will be presented. Conclusions: Patients with renal cancer who developed COVID19 held treatment more frequently and presented lower clinical benefit rates than non infected cases. Patients receiving immunotherapy required more frequent dose interruptions and longer hospitalizations than cases on antiangiogenics. These results point to an impact of SARS-CoV2 in renal cancer outcome. Therapies administered to treat renal cancer, could play a role in the evolution of COVID19.