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, Poly ADP-ribose polymerase inhibitor, Renal cell carcinoma, Renal medullary cancer, Metastatic, Programmed death-ligand 1, Succinate dehydrogenase deficient, SMARCB1, Von Hippel-Lindau altered
1. Introduction
The treatment landscape for patients with advanced clear cell renal cell carcinoma (ccRCC) consists of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and immune checkpoint blockade (ICB). Combination therapy yields durable tumor responses in some patients, but most will ultimately exhaust these agents, and serial retreatment with TKIs loses efficacy over time [1]. While options for less common non-ccRCC entities have improved over the years, rational, tailored strategies are still lacking [2].
A hallmark of ccRCC is Von Hippel-Lindau (VHL) inactivation occurring in the vast majority of tumors, resulting in downstream accumulation of hypoxia inducible factors (HIFs) and transcriptional upregulation of HIF-dependent pathways driving cell proliferation, cell migration, metabolism, and angiogenesis [3]. Studies support that VHL also plays a role in DNA repair and genomic integrity maintenance; consequently, VHL loss promotes genomic instability, may trigger DNA damage, and may enhance replication stress, all of which can culminate in replication mechanism collapse and cell cycle arrest [3–6]. In fact, VHL-altered ccRCC has 30–60% reductions of homologous and mismatch repair genes BRCA1, RAD51, MLH1, and FANCD2 [7].
Similarly, two rare renal cell carcinoma (RCC) subtypes are characterized by loss of function in fumarate hydratase (FH) and succinate dehydrogenase (SDH), the key components of oxidative and metabolic pathways. Oncometabolite accumulation of fumarate and succinate impairs DNA repair, resulting in genomic instability by competitively inhibiting α-ketoglutarate (αKG)-dependent dioxygenases, including lysine-specific demethylase 4A/B [8,9]. This leads to suppression of the homologous repair pathway [10]. Lastly, renal medullary carcinoma (RMC), a tumor uniformly characterized by SMARCB1 loss, has also been characterized to harbor increased DNA replication stress [11,12].
DNA repair is an essential mechanism for genomic integrity maintenance. Loss of one or more DNA damage response (DDR) pathways renders cells susceptible to DNA damage therapies [13]. Poly ADP-ribose polymerase (PARP) comprises enzymes that activate upon damaged DNA binding. The concept of exploiting synthetic lethal interactions between inherently impaired DNA repair and PARP inhibitors (PARPis) has been proved successful in human malignancies [13]. In keeping with the concepts outlined above, preclinical studies have found VHL-altered RCC, FH/SDH-deficient RCC, and RMC cancer cells to be vulnerable to PARPis [7,12,14].
As DNA damage is thought to increase neo-antigen repertoires leading to higher innate immune effector function and PARPis have been suggested to activate the cGAS/STING pathway essential in sensitivity to ICB, PARPis paired with ICB may achieve additive and/or synergistic effects [15–20]. We conducted a proof-of-concept clinical trial combining talazoparib, a potent oral PARP1/2 inhibitor approved in advanced breast cancer, and avelumab, a programmed death-ligand 1 (PD-L1) inhibitor with known efficacy in RCC, in molecularly defined RCC variants [21–23]. The safety and optimized dosing for this combination had previously been studied in a tumor-agnostic trial [24].
2. Patients and methods
2.1. Study design
This was a phase 2, investigator-initiated, single-institution trial of talazoparib plus avelumab (ClinicalTrials.gov ID: NCT04068831) conducted at Memorial Sloan Kettering Cancer Center. The study enrolled two cohorts: (1) ccRCC patients with VHL alteration and (2) FH- or SDH-deficient RCC patients. Several months into enrollment, an amendment expanded cohort 2 to include RMC patients due to newly emerging preclinical data [12]. Treatment was administered until disease progression or unacceptable toxicity. The study was sponsored by Pfizer Inc. (New York, NY, USA), which provided all study medications as part of an alliance between Pfizer and Merck (Rahway, NJ, USA). The study was approved by our institutional review board, and written informed consent was obtained from all patients.
2.2. Patients/eligibility
Patients in cohort 1 had ccRCC with tumors harboring mutations in VHL by next-generation sequencing (NGS) and maximally three prior lines of therapy, including at least one programmed cell death protein 1 (PD-1)/PD-L1 agent and one VEGFR inhibitor. Patients in cohort 2 had RCC with either FH or SDH loss by immunohistochemistry (IHC) or any alteration (somatic or germline) in FH or SDH by NGS, and had received at least one prior PD-1/PD-L1 agent or VEGFR inhibitor. RMC patients required histological confirmation (no IHC/NGS criteria required) and at least one line of chemotherapy. There were no maximum lines of therapy in cohort 2.
All histological diagnoses were confirmed by an expert genitourinary pathology review, and availability of archival tumor tissue was required. Other criteria included measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST), and adequate performance status and organ function at baseline.
2.3. Treatment and assessments
Avelumab was administered at an 800 mg flat dose intravenously every 14 d, after premedication with acetaminophen and diphenhydramine. Talazoparib was self-administered orally with a starting dose of 1 mg once daily. No dose reductions were recommended for avelumab, but dosing could be delayed or permanently discontinued if held >42 d. The protocol-guided dose modifications for talazoparib toxicity (1 > 0.75 > 0.5 >0.25 mg daily), with permanent discontinuation if held >28 d.
Radiographic tumor assessments with computerized tomography (and/or magnetic resonance chest/abdomen/pelvis imaging were performed every 8 wk for 12 mo, and then every 12 wk. The best response to treatment was determined by immune RECIST (iRECIST), and the date of progression was determined for the progression-free survival (PFS) analysis in secondary endpoint review by RECIST version 1.1 [25,26].
2.4. Safety
All patients were assessed for toxicity assessments as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 to describe the maximum intensity of adverse events. The assessment of the relationship of the adverse events with the study treatment was determined as related or nonrelated by the investigator.
2.5. Correlative endpoints
An NGS analysis was performed using the MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) platform as described previously [27]. This assay achieves pull-down capture with target-specific probes and germline comparison (from peripheral blood leukocytes) for exons from >500 cancer-related genes.
2.6. Statistical analysis
The primary endpoint was objective response rate (ORR) after 4 mo, assessed by iRECIST [25]. Patients were evaluable if they had received at least 50% of the planned doses for each agent during cycle 1. The secondary endpoints included PFS, defined as the time from the start of treatment until death or progression of disease; overall survival (OS), defined as the duration of time from the start of treatment until death of any cause; and safety/tolerability.
Cohort 1 followed an optimal Simon two-stage design (first stage = ten patients, second stage = 19 patients), allowing early study termination for a lack of preliminary efficacy. This design discriminated between response rates of 5% versus 20% with 80% power and a one-sided type I error of 5%. The probability of early termination under the null was 60%. The second cohort aimed to recruit 15 patients. Given the rarity of the cancers and the lack of defined standards of care, this sample size was not based on a formal delineation of a null hypothesis.
3. Results
Patients were accrued and treated between September 2019 and July 2022; the date of data cutoff was December 1, 2022.
3.1. Patient demographics and clinical characteristics
A summary is provided in Table 1. Cohort 1 enrolled ten patients (as per first Simon stage) with VHL-altered ccRCC; eight patients were male, and the median age was 62 yr. All patients had undergone nephrectomies, with a median of two prior lines of therapy (range 1, 3). All ten patients had somatic VHL mutations (Supplementary Fig. 1).
Table 1 –
Patient characteristics
| Cohort 1 (N = 10) | Cohort 2 (N = 8) | |
|---|---|---|
|
| ||
| Age at diagnosis (yr), median (range) | 62 (42, 77) | 40 (26, 58) |
| Sex, n (%) | ||
| Male | 8 (80) | 6 (75) |
| Female | 2 (20) | 2 (25) |
| Race, n (%) | ||
| White | 9 (90) | 3 (38) |
| Black | 0 (0) | 4 (50) |
| Asian | 1 (10) | 1 (12) |
| Histology and molecular profile, n (%) | ||
| VHL-altered RCC a | 10 (100) | – |
| VHL-altered RCC with sarcomatoid/rhabdoid features | 1 (10) | – |
| FH-deficient RCC b | ||
| Germline alteration | – | 3 (38) |
| Somatic alteration | – | 1 (12) |
| SDH-deficient RCC b | ||
| Somatic alteration | – | 1 (12) |
| Renal medullary carcinoma | – | 3 (38) |
| ECOG performance status, n (%) | ||
| 0 | 8 (80) | 3 (38) |
| 1 | 2 (20) | 3 (38) |
| 2 | 0 (0) | 2 (25) |
| IMDC risk classification, n (%) | ||
| Favorable | 6 (60) | 0 (0) |
| Intermediate | 4 (40) | 6 (75) |
| Poor | 0 (0) | 2 (25) |
| Prior nephrectomy, n (%) | 10 (100) | 7 (88) |
| Prior lines of treatment, n (%) | ||
| 1 | 4 (40) | 2 (25) |
| 2 | 2 (20) | 3 (38) |
| 3+ | 4 (40) | 3 (38) |
| Prior lines of immune checkpoint blockade, n (%) | ||
| 0 | 0 (0) | 2 (25) |
| 1 | 7 (70) | 5 (63) |
| 2+ | 3 (30) | 1 (12) |
| Number of disease sites, median (range) | 3 (1, 5) | 4 (1, 5) |
| Location of metastasis, n (%) | ||
| Lung | 8 (80) | 7 (88) |
| Lymph node | 5 (50) | 5 (62) |
| Liver | 3 (30) | 5 (62) |
| Bone | 3 (30) | 4 (50) |
| Adrenal | 3 (30) | 3 (38) |
| Pancreas | 4 (40) | 0 (0) |
| Soft tissue | 2 (20) | 1 (12) |
| Other kidney | 2 (20) | 1 (12) |
| Spleen | 0 (0) | 1 (12) |
| Brain | 1 (10) | 0 (0) |
VHL confirmed by somatic next-generation sequencing test.
FH and SDH deficiency confirmed either by somatic or germline next-generation sequencing test or by immunohistochemistry.
ECOG = Eastern Cooperative Oncology Group; FH = fumarate hydratase; IMDC = International mRCC Database Consortium; mRCC = metastatic RCC; RCC = renal cell carcinoma; SDH = succinate dehydrogenase; VHL = von Hippel-Lindau.
Cohort 2 enrolled eight patients: four with FH deficiency (one via IHC and three via NGS), one with SDH deficiency (via IHC), and three with RMC. In this cohort, nine patients were male, and the median age was 40 yr. Patients had received a median of three prior lines of therapy, including prior ICB in all FH and SDH patients and in one RMC patient. Owing to slow accrual and lack of efficacy, cohort 2 was closed early.
3.2. Treatment exposure
The median numbers of avelumab doses received for cohorts 1 and 2 were 8 (range: 1, 19) and 2 (range: 1, 14), respectively. Three patients in cohort 1 (30%) and two in cohort 2 (25%) missed at least one avelumab dose. The starting dose for talazoparib was 0.75 mg for three patients (18%), adjusted per renal function. Two patients in cohort 2 with early disease progression and death during cycle 1 did not have talazoparib compliance recorded. For the remaining patients, two in cohort 1 (20%) and two in cohort 2 (33%) missed at least one talazoparib dose.
3.3. Outcomes
All ten patients in cohort 1 discontinued therapy due to progressive disease. No objective responses were observed (Table 2). Seven patients (70%) achieved stable disease, and primary progression was seen in 20%. One patient suffered an infusion reaction to avelumab with subsequent heart failure exacerbation and received insufficient doses of talazoparib to be eligible for the primary endpoint. Treated with only talazoparib during cycle 2, this patient then experienced clinical progression. The median PFS was 3.5 mo (95% confidence interval [CI] 1.0, 3.9 mo) and the median OS was 21 mo (95% CI 2.7, 28 mo; Fig. 1). Figure 2A summarizes radiographic antitumor effects in the form of a waterfall plot depicting the maximal degree of response in the sum of target lesions.
Table 2 –
Study outcomes
| Cohort 1 (N = 10) | Cohort 2 (N = 8) | |
|---|---|---|
| Objective response rate (90% CI) | 0 (0, 28) | 0 (0, 31) |
| Best response, n (%) | ||
| Stable disease | 7 (70) | 2 (25) |
| Progressive disease | 2 (20) | 6 (75) |
| Not evaluable | 1 (10) | 0 (0) |
| Progression-free survival (mo), median (95% CI) | 3.5 (1.0, 3.9) | 1.2 (0.4, 2.9) |
| Overall survival (mo), median (95% CI) | 21 (2.7, 28) | 8.6 (0.7, 24) |
CI = confidence interval.
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.
All eight patients in cohort 2 also discontinued therapy due to progression. Several patients were taken off trial prior to the first scheduled imaging assessment due to rapid clinical deterioration. In this cohort, there were no objective responses, the median PFS was 1.2 mo (95% CI 0.4, 2.9 mo), and the median OS was 8.6 mo (95% CI 0.7, 24 mo).
3.4. Safety
Treatment-related adverse events (TRAEs) in the two cohorts are summarized in Table 3. The most common TRAEs of all grades were fatigue (61%), anemia (28%), nausea (22%), and headache (22%). Grade 3–4 TRAEs occurred in two patients with anemia and one patient each with fatigue, nausea, platelet count decrease, heart failure, and neutrophil count decrease. No grade 5 events occurred. Treatment-emergent adverse events are summarized in Supplementary Table 1.
Table 3 –
Treatment-related adverse events
| Adverse event | All grades, n (%) | Grade 3–4, n (%) |
|---|---|---|
|
| ||
| Fatigue | 11 (61) | 1 (6) |
| Anemia | 5 (28) | 2 (11) |
| Nausea | 4 (22) | 1 (6) |
| Headache | 4 (22) | – |
| Dyspnea | 3 (17) | – |
| Constipation | 3 (17) | – |
| Cough | 3 (17) | – |
| Platelet count decreased | 2 (11) | 1 (6) |
| Anorexia | 2 (11) | – |
| Vomiting | 2 (11) | – |
| Diarrhea | 2 (11) | – |
| Dry mouth | 2 (11) | – |
| Insomnia | 2 (11) | – |
| Rash maculopapular | 2 (11) | – |
| Heart failure | 1 (6) | 1 (6) |
| Neutrophil count decreased | 1 (6) | 1 (6) |
Possibly, probably, or definitely treatment-related adverse events occurring with at least 10% all-grade frequency (at least two patients) or any grade 3 or 4 frequency are shown.
3.5. Tissue analysis investigating DDR mutations
Somatic tumor profiling by NGS was performed for 16 patients. Six patients harbored DDR mutations (ATM, BRIP1, CHEK2, ERCC5, POLE, RAD50, and RECQL4); only one achieved a decrease in size of the target lesion, but not sufficient to qualify as a RECIST response (Fig. 2B). A complete summary of molecular data is provided in Figure 3.
Fig. 3 –
Oncoprint.
FH = fumarate hydratase; RMC = renal medullary carcinoma; SDH = succinate dehydrogenase; VUS = variant of uncertain significance.
4. Discussion
This phase 2 study of talazoparib and avelumab in patients with metastatic ccRCC, FH/SDH-deficient RCC, or RMC did not meet its primary endpoint, and no patients achieved an objective response within 4 mo of treatment.
Genomic instability is inherent to several subtypes of kidney cancer and provided the molecular rationale for the present study. Recent studies have demonstrated that many RCC tumors have conferred “BRCAness,” the notion that DDR-associated genes other than BRCA1 and BRCA2 may confer similar defects in DNA repair [28,29]. VHL-altered ccRCCs have been shown to have lower expression of homologous repair and mismatch repair genes [7]. Generally, cancer cells have been shown to be increasingly sensitive to PARPis in hypoxic environments, and ccRCC tumors exhibit hypoxic pathway upregulation through HIF-dependent pathways [30]. Germline and somatic loss FH and SDH deficiency result in inhibition of αKG-dependent dioxygenases and consequent accumulation of DNA double-stranded breaks through homologous recombination impairment [10,13]. Similarly, recent preclinical data have suggested therapeutic vulnerability to drugs targeting DDR pathways in RMC [12].
PARPis have been proved effective in DDR impaired breast, ovarian, prostate, and pancreas cancers [31] and, more recently, in select DDR proficient settings [32]. Although preclinical evidence has shown that RCCs harboring mutations in BAP1 and PBRM1, FH- and SDH-deficient tumors, and RMC tumors are all susceptible to PARPis, this therapeutic modality has not yet been clinically validated in any of these entities [7,12,14,18,33].
Preclinically, synergism between PARP inhibition and ICB has been proposed through various mechanisms [15–20,34,35]; yet, in a recent tumor-agnostic clinical trial exploring the combination of PARP and PD-L1 inhibitors in BRCA1/2- and ATM-altered cancers, neither cohort met the prespecified target ORR [24]. Our study is the first trial reported to assess this approach in metastatic kidney cancer and failed to confirm efficacy despite manageable tolerability of the regimen.
Beyond its significance as the first reported clinical trial of PARPis in these cancers, the trial is novel in that it explored targeted treatments in kidney cancers of defined molecular backgrounds. Up until now, pivotal trials in sporadic RCC have never enrolled patients as per oncogenomic criteria. Belzutifan, an inhibitor of HIF2-alpha, was approved in ccRCC patients with a VHL syndromic background based on a phase 2 trial, thus constituting the first mutation-based registration in the field [36]. Our study demonstrates that panel testing, now broadly accessible, can successfully be integrated in early-phase study design. Retrospective efforts and correlative analyses from large-scale clinical trials have helped delineate molecular subtypes in ccRCC and non-ccRCC [37–39], and select studies are now aiming to direct the choice of therapy per such predefined molecular stratification [40–42]. Such efforts are central to help individualize and improve treatment in patients with common and rare kidney cancers.
Cohort 2 explored treatment in three defined entities within the large pool of “non–clear cell” kidney cancers. For patients with non–clear cell histologies, there is a paucity of subtype-specific prospective data, with clinical rationale typically being derived from phase 2 trials conducted across all non–clear cell histologies or retrospective series [43,44]. In patients with papillary variant RCC and underlying FH deficiency (included in cohort 2 of this study), combination therapies including bevacizumab/erlotinib, bevacizumab/everolimus, and cabozantinib/nivolumab have shown promise [45–47]. For patients with RCC and underlying SDH deficiency, outcomes are generally poor and there are no prospective data to guide standard treatments [48]. Prognosis in patients with RMC is also uniformly guarded, and treatment guidelines recommend combination cytotoxic chemotherapies as first-line options. Various targeted agents, including VEGFR TKIs, mammalian target of rapamycin (mTOR) pathway inhibitors, and proteasome inhibitors, are being used in chemotherapy-pretreated patients with limited efficacy [49,50].
Several ongoing trials are further evaluating PARPis in different contexts and combinations in kidney cancer, including a trial of olaparib in pretreated patients harboring DDR gene mutations (ClinicalTrials.gov identifier: NCT03786796). Other trials are testing PARPis in DDR-deficient cancers across various solid tumors (ClinicalTrials.gov identifiers: NCT03207347 and NCT03682289). Notably, none of the six patients with somatic DDR alterations derived benefit from treatment on our trial, nor did we see responses in five patients harboring alterations in PBRM1 [18].
Our study was limited by the small sample size, first and foremost. A low level of activity, for example, <10% ORR, could have therefore been missed, although the clinical relevance of such a low response rate would be debatable. Furthermore, nearly all patients had previously progressed on anti–PD-1/PD-L1 therapies, and therefore the potential benefit of a second anti–PD-L1 inhibitor is uncertain.
5. Conclusions
In conclusion, in this phase 2, single-institution study, the combination of talazoparib and avelumab in genomically defined patient cohorts of treatment-refractory metastatic kidney cancer was reasonably well tolerated but did not meet the primary endpoint, and no patients achieved an ORR after 4 mo of treatment.
Supplementary Material
Financial disclosures:
Ritesh R. Kotecha certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Ritesh R. Kotecha: consulting/advisory board—Eisai, and research funding—Pfizer, Novartis, Allogene Therapeutics, Exelixis, and Takeda. Sahil D. Doshi, Andrea Knezevic, and Joshua Chaim: none. Ying-Bei Chen: consulting—Inspirna, Inc. Rachel Jacobi and Mark Zucker: none. Ed Reznik: consulting—Xontogeny, LLC. Deaglan McHugh: consulting—Progenics. Neil Shah: consulting—Merck, Aravive, Exelixis, MetNet, and MJH Oncology; research/institutional support—Aravive and Exelixis. Emily Feld: none. David H. Aggen: consulting fees/research funding—Seattle Genetics, Astellas, and Merck; consulting fees—Bristol Myers Squibb, Century Therapeutics, and 2Seventy Bio; honoraria—Curio Life Sciences and MJH Life Sciences. William Rafelson, Han Xiao, and Maria I. Carlo: none. Darren R. Feldman: consulting—Telix and BioNTech; research funding—Telix, Decibel Therapeutics, and Astellas; royalties—UpToDate. Chung-Han Lee: consulting—Amgen, Aveo, BMS, Exelixis, Eisai, Merck, Pfizer, EMD Serono, and Cardinal Health; research funds to institute—AstraZeneca, BMS, Calithera, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer; honoraria—AiCME, IDEOlogy Health, Intellisphere, Medscape, MJH, and Research to Practice. Robert J. Motzer: consulting—AstraZeneca, Aveo, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Pfizer, and Merck; research funding—Aveo, Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Novartis, Pfizer, and Merck. Martin H. Voss: consulting/advisory board—Eisai, Exelixis, Merck, Calithera, Aveo, Genentech, Oncorena, Affimed, MICU Rx Aravive, onQuality, AstraZeneca, and Mertelsmann Foundation; research funding—Pfizer, BMS, and Genentech.
Funding/Support and role of the sponsor:
This study was an investigator-initiated study supported by Pfizer (WI244994), as part of an alliance between Pfizer and Merck (CrossRef Funder ID: 10.13039/100009945). Ritesh R. Kotecha is also supported, in part, by the Academy of Kidney Cancer Investigators of the CDMRP/DOD (KC200127). The research was also supported, in part, by the Memorial Sloan Kettering Cancer Center’s National Institutes of Health Support Grant/Core (P30-CA008748).
Footnotes
In a phase 2 trial evaluating poly ADP-ribose polymerase inhibitors and programmed death-ligand 1 inhibition in two treatment-refractory, genomically defined, advanced kidney cancer cohorts—(1) Von Hippel-Lindau–altered renal cell carcinoma (RCC) and (2) fumarate hydratase- or succinate dehydrogenase-deficient RCC and renal medullary carcinoma, no objective responses were seen.
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