Cabozantinib Safety With Different Anticoagulants in Patients With Renal Cell Carcinoma.

BACKGROUND: In patients with renal cell carcinoma (RCC) on cabozantinib, venous thromboembolism (VTE) management remains challenging due to limited safety data regarding direct oral anticoagulants (DOACs) use in conjunction with cabozantinib. We investigated the safety of cabozantinib with different anticoagulants in patients with RCC. METHODS: In this retrospective multicenter study (9 sites), patients with advanced RCC were allocated into 4 groups: (1) cabozantinib without anticoagulation, cabozantinib with concomitant use of (2) DOACs, (3) low molecular weight heparin (LMWH), or (4) warfarin. The primary safety endpoint was the proportion of major bleeding events (defined per International Society on Thrombosis and Hemostasis criteria). The primary efficacy endpoint was the proportion of new/recurrent VTE while anticoagulated. RESULTS: Between 2016 and 2020, 298 patients with RCC received cabozantinib (no anticoagulant = 178, LMWH = 41, DOAC = 64, and warfarin = 15). Most patients had clear cell histology (78.5%) and IMDC intermediate/poor disease (78.2%). Cabozantinib was first, second, or ≥ third line in 21.8%, 31.9%, 43.3% of patients, respectively. Overall, there was no difference in major bleeding events between the no anticoagulant, LMWH, and DOAC groups (P = .088). Rate of new/recurrent VTE was similar among anticoagulant groups. Patients with a VTE had a statistically significantly worse survival than without a VTE (HR 1.48 [CI 95% 1.05-2.08, P = .02]). CONCLUSION: This real-world cohort provides first data on bleeding and thrombosis complications in patients with RCC treated with cabozantinib with or without concurrent anticoagulation. DOACs appear safe for VTE treatment for patients with RCC on cabozantinib, but optimized anticoagulation management, including individualized risk-benefit discussion, remains important in clinical practice.

Outcomes of patients with advanced non-clear cell renal cell carcinoma treated with first-line immune checkpoint inhibitor therapy.

BACKGROUND: Immune checkpoint inhibitors (ICI) have demonstrated impressive activity in metastatic clear-cell renal cell carcinoma (ccRCC) and have become standard treatment options for patients with advanced disease. Data supporting the effectiveness of ICI-based therapy in advanced non-clear cell RCC (nccRCC) is more limited. METHODS: We performed a retrospective analysis using the International Metastatic RCC Database Consortium (IMDC) to evaluate the outcomes of patients with advanced nccRCC. Patients were classified into three groups based on first-line therapy: ICI-based therapy (monotherapy or combination), vascular endothelial growth factor (VEGF) inhibitor monotherapy, or mammalian target of rapamycin (mTOR) inhibitor monotherapy. The primary outcome was overall survival (OS). Secondary outcomes were time to treatment failure (TTF) and objective response rate (ORR). We used the Kaplan-Meier method to compare OS and TTF between treatment groups and Cox proportional hazards models to adjust for prognostic covariates. RESULTS: We identified a total of 1145 patients with metastatic nccRCC. The most common subtype was papillary RCC (54.9%). For first-line therapy, 74.3% received VEGF monotherapy, 15% received mTOR monotherapy, and 10.7% received ICI-based therapy. Median OS in the ICI group was 28.6 months, versus 16.4 months in the VEGF group and 12.2 months in the mTOR group. Median TTF in the ICI group was 6.9 months, versus 5.0 months in the VEGF group and 3.9 months in the mTOR group. ORR was 27.2% in the ICI group, 14.5% in the VEGF group, and 9% in the mTOR group. After adjusting for the IMDC risk group, histological subtype, and age, the hazard ratio for OS was 0.57 (95% CI 0.42-0.78, p < 0.0001) for ICI versus VEGF and 0.50 (95% CI 0.36-0.71, p < 0.0001) for ICI versus mTOR. CONCLUSIONS: In advanced nccRCC, first-line ICI-based treatment appears to be associated with improved OS compared to VEGF and mTOR targeted therapy. These results should be confirmed in prospective randomised trials.

Avelumab Combined with Stereotactic Ablative Body Radiotherapy in Metastatic Castration-resistant Prostate Cancer: The Phase 2 ICE-PAC Clinical Trial.

BACKGROUND: Immune checkpoint inhibitor monotherapy in metastatic castration-resistant prostate cancer (mCRPC) has produced modest results. High-dose radiotherapy may be synergistic with checkpoint inhibitors. OBJECTIVE: To evaluate the efficacy and safety of the PD-L1 inhibitor avelumab with stereotactic ablative body radiotherapy (SABR) in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: From November 2017 to July 2019, this prospective phase 2 study enrolled 31 men with progressive mCRPC after at least one prior androgen receptor-directed therapy. Median follow-up was 18.0 mo. INTERVENTION: Avelumab 10 mg/kg intravenously every 2 wk for 24 wk (12 cycles). A single fraction of SABR (20 Gy) was administered to one or two disease sites within 5 d before the first and second avelumab treatments. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the disease control rate (DCR), defined as a confirmed complete or partial response of any duration, or stable disease/non-complete response/non-progressive disease for ≥6 mo (Prostate Cancer Clinical Trials Working Group 3-modified Response Evaluation Criteria in Solid Tumours version 1.1). Secondary endpoints were the objective response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS), and safety. DCR and ORR were calculated using the Clopper-Pearson exact binomial method. RESULTS AND LIMITATIONS: Thirty-one evaluable men were enrolled (median age 71 yr, 71% with ≥2 prior mCRPC therapy lines, 81% with >5 total metastases). The DCR was 48% (15/31; 95% confidence interval [CI] 30-67%) and ORR was 31% (five of 16; 95% CI 11-59%). The ORR in nonirradiated lesions was 33% (four of 12; 95% CI 10-65%). Median rPFS was 8.4 mo (95% CI 4.5-not reached [NR]) and median OS was 14.1 mo (95% CI 8.9-NR). Grade 3-4 treatment-related adverse events occurred in six patients (16%), with three (10%) requiring high-dose corticosteroid therapy. Plasma androgen receptor alterations were associated with lower DCR (22% vs 71%, p = 0.13; Fisher's exact test). Limitations include the small sample size and the absence of a control arm. CONCLUSIONS: Avelumab with SABR demonstrated encouraging activity and acceptable toxicity in treatment-refractory mCRPC. This combination warrants further investigation. PATIENT SUMMARY: In this study of men with advanced and heavily pretreated prostate cancer, combining stereotactic radiotherapy with avelumab immunotherapy was safe and resulted in nearly half of patients experiencing cancer control for 6 months or longer. Stereotactic radiotherapy may potentially improve the effectiveness of immunotherapy in prostate cancer.

Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials.

BACKGROUND: Immuno-oncology (IO)-based therapies have been approved based on randomised clinical trials, yet a significant proportion of real-world patients are not represented in these trials. We sought to compare the outcomes of trial-ineligible vs. -eligible patients with advanced solid tumours treated with first-line (1L) IO therapy. PATIENTS AND METHODS: Using the International Metastatic Renal Cell Carcinoma (RCC) Database Consortium and the Alberta Immunotherapy Database, patients with advanced RCC, non-small-cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition-based therapy were included. Trial eligibility was retrospectively determined as per commonly used exclusion criteria. The outcomes of interest were overall survival (OS), overall response rate (ORR), treatment duration (TD) and time to next treatment (TTNT). RESULTS: A total of 395 of 1241 (32%) patients were deemed trial-ineligible. The main reasons for ineligibility based on preselected exclusion criteria were Karnofsky performance status <70%/Eastern Cooperative Oncology Group performance status >1 (40%, 158 of 395), brain metastases (32%, 126 of 395), haemoglobin < 9 g/dL (16%, 63 of 395) and estimated glomerular filtration rate <40 mL/min (15%, 61 of 395). Between the ineligible vs. eligible groups, the median OS, ORR, median TD and median TTNT were 10.2 vs. 39.7 months (p < 0.01), 36% vs. 47% (p < 0.01), 2.7 vs. 6.9 months (p < 0.01) and 6.0 vs. 16.8 months (p < 0.01), respectively. Subgroup analyses showed statistically significant inferior OS, TD and TTNT for trial-ineligible vs. -eligible patients across all tumour types. Adjusted hazard ratios for death in RCC, NSCLC and melanoma were 1.84 (95% confidence interval [CI] 1.22-2.77), 2.21 (95% CI 1.58-3.11) and 1.82 (95% CI 1.21-2.74), respectively.. CONCLUSIONS: Thirty-two percent of real-world patients treated with contemporary 1L IO-based therapies were ineligible for clinical trials. Although one-third of the trial-ineligible patients responded to treatment, the overall trial-ineligible population had inferior outcomes than trial-eligible patients. These data may guide patient counselling and temper expectations of benefit.

Efficacy of immune-checkpoint inhibitors (ICI) in the treatment of older adults with metastatic renal cell carcinoma (mRCC) - an International mRCC Database Consortium (IMDC) analysis.

OBJECTIVE: Older adults with metastatic renal cell carcinoma(mRCC) are underrepresented in immune-checkpoint inhibitor(ICI) registration trials. Here we compare the efficacy of ICI treatments in older vs. younger adults with mRCC. METHODS: Using the International mRCC Database Consortium(IMDC), patients treated with a PD(L)-1 based ICI were identified. Older adult was defined as ≥70-years at the time of treatment. Descriptive statistics were summarized in means, medians, and proportions. Effectiveness endpoints included overall survival (OS), time-to-treatment failure(TTF), time-to-next treatment(TNT), and overall response rate(ORR). Hazards ratios were adjusted(aHR) for IMDC risk factors, histology, line of treatment and older age. RESULTS: Of 1427 included patients, 397(28%) were older adults. ICI was used as 1st line(1 L) in 40%, 2nd line(2 L) in 49% and 3rd line(3 L) in 11% of patients. In univariable analysis, older adults had inferior OS compared to younger adults(25.1 m vs. 30.8 m, p < 0.01). There were no significant differences in TTF (6.9 m vs. 6.9 m, p = 0.4) or TNT(9.1 m vs 10 m, p = 0.3) between groups. In multivariable analyses, older age was not independently associated with worse OS(aHR = 1.02, p = 0.8), TTF(aHR = 0.95, p = 0.6) or TNT(aHR = 0.93, p = 0.5). Older adults had a lower ORR compared to younger adults(24% vs. 31%, p = 0.01), which was mainly driven by responses in 1 L(31% vs. 44%, p = 0.02) and not observed in 2 L/3 L. CONCLUSIONS: After multivariable analyses, older adults with mRCC treated with ICI had no difference in OS, TTF or TNT when compared to younger adults. Our data support that chronological older age should not preclude patients from receiving ICI based therapies.