A Phase 2 Trial of Talazoparib and Avelumab in Genomically Defined Metastatic Kidney Cancer

Abstract

Background: Although different kidney cancers represent a heterogeneous group of malignancies, multiple subtypes including Von Hippel-Lindau (VHL)-altered clear cell renal cell carcinoma (ccRCC), fumarate hydratase (FH)- and succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC), and renal medullary carcinoma (RMC) are affected by genomic instability. Synthetic lethality with poly ADP-ribose polymerase inhibitors (PARPis) has been suggested in preclinical models of these subtypes, and paired PARPis with immune checkpoint blockade (ICB) may achieve additive and/or synergistic effects in patients with previously treated advanced kidney cancers.

Objective: To evaluate combined PARPi + ICB in treatment-refractory metastatic kidney cancer.

Design, setting, and participants: We conducted a single-center, investigator-initiated phase 2 trial in two genomically selected advanced kidney cancer cohorts: (1) VHL-altered RCC with at least one prior ICB agent and one vascular endothelial growth factor (VEGF) inhibitor, and (2) FH- or SDH-deficient RCC with at least one prior ICB agent or VEGF inhibitor and RMC with at least one prior line of chemotherapy.

Intervention: Patients received talazoparib 1 mg daily plus avelumab 800 mg intravenously every 14 d in 28-d cycles.

Outcome measurements and statistical analysis: The primary endpoint was objective response rate (ORR) by Immune Response Evaluation Criteria in Solid Tumors at 4 mo, and the secondary endpoints included progression-free survival (PFS), overall survival, and safety.

Results and limitations: Cohort 1 consisted of ten patients with VHL-altered ccRCC. All patients had previously received ICB. The ORR was 0/9 patients; one patient was not evaluable due to missed doses. In this cohort, seven patients achieved stable disease (SD) as the best response. The median PFS was 3.5 mo (95% confidence interval [CI] 1.0, 3.9 mo). Cohort 2 consisted of eight patients; four had FH-deficient RCC, one had SDH-deficient RCC, and three had RMC. In this cohort, six patients had previously received ICB. The ORR was 0/8 patients; two patients achieved SD as the best response and the median PFS was 1.2 mo (95% CI 0.4, 2.9 mo). The most common treatment-related adverse events of all grades were fatigue (61%), anemia (28%), nausea (22%), and headache (22%). There were seven grade 3-4 and no grade 5 events.

Conclusions: The first clinical study of combination PARPi and ICB therapy in advanced kidney cancer did not show clinical benefit in multiple genomically defined metastatic RCC cohorts or RMC.

Patient summary: We conducted a study to look at the effect of two medications, talazoparib and avelumab, in patients with metastatic kidney cancer who had disease progression on standard treatment. Talazoparib blocks the normal activity of molecules called poly ADP-ribose polymerase, which then prevents tumor cells from repairing themselves and growing, while avelumab helps the immune system recognize and kill cancer cells. We found that the combination of these agents was safe but not effective in specific types of kidney cancer.

Keywords: Fumarate hydratase deficient; Immunotherapy; Metastatic; Poly ADP-ribose polymerase inhibitor; Programmed death-ligand 1; Renal cell carcinoma; Renal medullary cancer; SMARCB1; Succinate dehydrogenase deficient; Von Hippel-Lindau altered.

Fig. 1 –

Progression-free and overall survival in cohorts 1 and 2. Progression-free survival: All patients had disease progression or otherwise died during study follow-up. The median PFS in (A) cohort 1 and (B) cohort 2 was 3.5 mo (95% CI 1.0, 3.9) and 1.2 mo (95% CI 0.4, 2.9), respectively. Overall survival: There were eight deaths in (C) cohort 1 and seven deaths in (D) cohort 2. The median OS in cohorts 1 and 2 was 21 mo (95% CI 2.7, 28) and 8.6 mo (95% CI 0.7, 24), respectively. Two survivors in cohort 1 were followed for 31 and 41 mo and one survivor in cohort 2 was followed for 37 mo. CI = confidence interval; OS = overall survival; PFS = progression-free survival.

Fig. 2 –

(A) Maximum change from baseline in target lesions in cohorts 1 and 2. (B) Maximum change from baseline in target lesions of evaluable patients stratified by the presence of a DNA damage repair (DDR) mutation. AF = allelic frequency; FH = fumarate hydratase; RMC = renal medullary carcinoma; SDH = succinate dehydrogenase; VHL = Von Hippel-Lindau. ^a One patient from cohort 1 was not evaluable for response assessment due to insufficient exposure to therapy. ^b Four patients from cohort 2 with rapid clinical progression were not evaluable for response assessment. ^c Mutations with allelic frequency that are not included are heterozygous germline mutations.

Fig. 3 –

Oncoprint. FH = fumarate hydratase; RMC = renal medullary carcinoma; SDH = succinate dehydrogenase; VUS = variant of uncertain significance.