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Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non–clear cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation are limited. In this multicenter analysis, we explored the efficacy of PD-1/PD-L1 inhibitors in patients with nccRCC or sarcomatoid/rhabdoid differentiation. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate. Secondary endpoints include time-to-treatment failure (TTF), overall survival (OS), and biomarker correlates. Forty-three patients were included: papillary (n = 14; 33%), chromophobe (n = 10; 23%), unclassified (n = 9; 21%), translocation (n = 3; 7%), and ccRCC with sarcomatoid differentiation (n = 7, 16%). Of those 43 patients, 11 patients (26%) had sarcomatoid and/or rhabdoid differentiation (n = 7 with ccRCC; n = 4 nccRCC). Overall, 8 patients (19%) objectively responded, including 4 patients (13%) who received PD-1/PD-L1 monotherapy. Responses were observed in patients with ccRCC with sarcomatoid and/or rhabdoid differentiation (n = 3/7, 43%), translocation RCC (n = 1/3, 33%), and papillary RCC (n = 4/14, 29%). The median TTF was 4.0 months [95% confidence interval (CI), 2.8–5.5] and median OS was 12.9 months (95% CI, 7.4–not reached). No specific genomic alteration was associated with clinical benefit. Modest antitumor activity for PD-1/PD-L1–blocking agents was observed in some patients with nccRCC. Further prospective studies are warranted to investigate the efficacy of PD-1/PD-L1 blockade in this heterogeneous patient population. Cancer Immunol Res; 6(7); 758–65. ©2018 AACR.

Includes: Table 1S. Baseline patient and disease characteristics. Table 2S. Tumor mutation burden status. Table 3S. PDL1 expression data. Figure 1S. Overall survival for the total cohort.

Figure for online supplement

Purpose: This study investigates the biologic activity of radium-223 with VEGF-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases.Patients and Methods: Fifteen treatment-naïve patients (n = 15) received pazopanib 800 mg orally once daily, and 15 previously treated patients received sorafenib 400 mg orally twice daily. Radium-223 55 kilobecquerel/kg was administered concurrently every 4 weeks for up to six infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin, and bone-specific alkaline phosphatase) compared with baseline. Secondary endpoints included safety, rate of symptomatic skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use, and quality of life. Exploratory analysis of tumor genomic alterations was performed.Results: Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases, and 83% had a history of SSE prior to enrollment. No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time.Conclusions: Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in aRCC with skeletal metastases. Clin Cancer Res; 24(17); 4081–8. ©2018 AACR.

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Purpose:Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC.Patients and Methods:Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints.Results:Twenty-four patients were enrolled in the dose-escalation (n = 16) and dose-expansion (n = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ≥3 events (25%) included transaminitis (n = 2), fatigue (n = 1), hypertension (n = 1), pulmonary embolism (n = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8–21.2). Pharmacokinetics analysis at the MTD (n = 12) revealed a mean Cmaxss of 104 ± 45 ng/mL and AUCτss of 1,000 ± 476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (Cmaxss, 315 ng/mL and AUCτss, 3,817 ng•h/mL).Conclusions:Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.

Purpose:Atezolizumab [anti–programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC.Patients and Methods:This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments.Results:All 35 evaluable patients [median age, 68 years (range, 45–83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9–not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34–70); 2-year OS was 35.9% (95% CI: 13–59). Median follow-up was 13.0 months (range, 1.2–28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy.Conclusions:Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.

SRF388 is a first-in-class, anti-IL-27 antibody developed to enhance immune responses within the tumor microenvironment. Preclinical studies have demonstrated that IL-27 pathway blockade can inhibit tumor growth in mouse models of liver cancer and lung cancer metastases. There is also evidence that IL-27 pathway inhibition is accompanied by activation of the innate and adaptive arms of the immune system. An ongoing Phase I trial has shown good tolerability at all dose levels tested and preliminary monotherapy antitumor activity with SRF388 (NCT04374877). Here, we describe the preclinical and clinical data used to select a RP2D and characterize cytokine and chemokine changes observed in patients after treatment with SRF388. To guide selection of the RP2D, the relationship between maximal effective dose (MaxED), pharmacokinetics (PK), and whole blood inhibition of IL-27-mediated phosphorylation of STAT1 by SRF388 was evaluated in a mouse model of liver cancer. The concentration of SRF388 associated with optimal antitumor activity was ~20-fold above the concentration needed for complete inhibition (> 90%) of whole blood phosphorylated STAT1 (pSTAT1). These PK and activity relationships were also defined in patients during the dose-escalation phase of the trial and integrated with safety and efficacy data to select a monotherapy RP2D. In patients, PK were linear, no dose-limiting toxicities were reported, complete pSTAT1 inhibition was achieved throughout the first cycle at 0.3 mg/kg, and 1 patient experienced a confirmed partial response per RECIST version 1.1 at a dose of 10 mg/kg. In the MaxED mouse model, the area under the concentration versus time curve (AUC) associated with significant antitumor activity was 1720 day*μg/mL. In patients, the corresponding target AUC was achieved clinically at 10 mg/kg after a single dose of SRF388. Changes in the concentration of several serum cytokines and chemokines were observed after SRF388 treatment including an increase in IL-27, a phenomenon described for other anti-cytokine antibodies due to altered clearance of the cytokine-antibody complex. Changes in a subset of other serum cytokines/chemokines correlated with a reduction in target lesion size. Taken together, these data support the selection of a monotherapy RP2D of 10 mg/kg intravenously every 4 weeks for SRF388. These data highlight how complementary strategies utilizing preclinical and clinical biomarker evaluations can be employed to establish a monotherapy RP2D and assess biological activity of a first-in-class anti-cytokine antibody, SRF388, for patients with cancer. Citation Format: Jonathan A. Hill, Kerry F. White, Matthew Rausch, Jou-Ku Chung, Amita Patnaik, Aung Naing, Daniel Morgensztern, Charlene M. Mantia, Nizar M. Tannir, Lon S. Smith, Beth Bowers, Alex Alika, Lauren C. Harshman, Benjamin H. Lee. Determination of a recommended Phase 2 dose (RP2D) for SRF388, a first-in-class IL-27-blocking antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1137.

2501 Background: The immunoregulatory cytokine IL-27 upregulates inhibitory immune checkpoint receptors (eg, PD-L1, TIGIT) and downregulates proinflammatory cytokines (eg, IFNγ, TNFα). SRF388 is a fully human IgG1 blocking antibody to IL-27 with potential to promote immune activation in the tumor microenvironment. A phase 1 study was conducted to establish the preliminary safety of SRF388 and to identify recommended phase 2 doses (RP2D) suitable for monotherapy and combination expansions (NCT04374877). Methods: The dose-escalation study (accelerated single patient followed by standard 3+3) enrolled patients (pts) with advanced treatment-refractory solid tumors. Upon RP2D selection, monotherapy and combination expansions opened for treatment-refractory clear cell renal cell cancer (ccRCC), hepatocellular cancer (HCC), and non-small cell lung cancer. SRF388 was administered IV every 4 weeks (wks) as monotherapy and every 3 wks with pembrolizumab. Tumor response was assessed by RECIST1.1. Results: The monotherapy dose-escalation enrolled 29 pts with doses ranging from 0.003 to 20 mg/kg. Median age was 64 years. Most pts were female (62%) with ECOG PS of 1 (72%). Approximately 80% had prior PD-(L)1 blockade, and 48% had ≥4 prior therapies. Treatment-related adverse events (TRAEs) occurred in 21%, and all were low grade. Fatigue was the only TRAE reported in ≥10% (n = 3). No dose-limiting toxicities (DLTs) or Grade ≥3 TRAEs were observed. Median time on study was 9 wks (range 0–59). One patient with highly treatment-refractory NSCLC experienced a confirmed partial response (PR) at 8 wks that was durable for 20 wks. Nine pts (31%) experienced disease stabilization at 8 wks, with 6 of 9 exhibiting durable disease control at 6 months. Of the 7 pts with ccRCC in the dose-escalation portion of the trial, 3 (43%) experienced durable disease control for ≥20 wks (range: 20-32). With doses up to 20 mg/kg, SRF388 PK remain linear with an estimated T1/2 of 10-12 days. PK characteristics and safety profile support dosing every 3 or 4 wks. Based on safety, tolerability, PK, peripheral pSTAT1 inhibition, and preliminary efficacy, 10 mg/kg was selected as the RP2D. Both the pembrolizumab safety cohort (n = 10) and Stage 1 of the ccRCC monotherapy expansion (n = 17) have fully enrolled. Of the 10 evaluable pts with ccRCC, 1 confirmed monotherapy PR has been reported, enabling Stage 2 initiation. Changes in several serum cytokines and chemokines were observed after SRF388 administration, including expected increase in circulating IL-27 levels. Conclusions: Results of IL-27 pathway blockade with a first-in-class therapeutic demonstrates that SRF388 has good tolerability with encouraging preliminary antitumor activity as a monotherapy. Updated data, including safety and clinical outcomes as well as correlative biomarker analyses, will be presented. Clinical trial information: NCT04374877.

Importance Patients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in metastatic RCC, but its effect on brain metastases remains unclear. Objective To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC. Design, Setting, and Participants This retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy. Exposures Receipt of cabozantinib monotherapy at any line of treatment. Main Outcomes and Measures Intracranial radiological response rate by modified Response Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib. Results Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed. Conclusions and Relevance In this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.