Costello, Brian A.

409 Background: For patients with metastatic renal cell carcinoma (RCC), metastasis-directed local therapies can delay progression and need to initiate/switch systemic therapy. We examined our experience treating lung or mediastinal metastases from RCC with radiotherapy (RT). Methods: We reviewed patients with lung or mediastinal metastases from RCC treated with RT. Overall survival (OS) and local control (LC) was measured from the start of RT using the Kaplan-Meier method. Results: Seventy-one patients were treated with RT for 89 lung or mediastinal metastases. Median follow-up was 2.0 years (range 0.02-11.4 years) after RT for surviving patients. Most patients were male (n=53, 74.6%). Median age was 58.4 years at initial diagnosis. Histology was most frequently clear cell carcinoma (n=62, 89.9%). At the time of treatment, 18 patients (25.4%) had 1-3 metastases, and the remainder (74.6%) had 4 or more metastases. Forty-one patients (57.5%) received systemic therapy prior to thoracic radiation. Initial systemic therapy was most commonly sunitinib (45%) or pazopanib (32.5%). Median time from starting systemic therapy to initiation of radiation was 2.0 years. Fifty-eight lung metastases and 31 mediastinal metastases were treated with a median 5 fractions (range 1-40), to a median total dose of 4800 cGy (range 400-7000), with a median fraction size of 500 cGy (range 150-2000). Thirty-three lesions were treated with concurrent systemic therapy, which was most commonly nivolumab (n=16). Of 89 treated lesions, 11 (12%) had local tumor recurrence, at a median of 1.6 years (range 0.4-2.9 years) after initiation of radiation. 1, 3, and 5 year MC (metastasis control) were 96.6%, 83.5% and 67.9%, respectively. Nine patients were treated with radiation in order to delay initiation of systemic therapy. Of these, 3 eventually received systemic therapy, initiated at a median 2.5 years after radiation. At last follow-up, 41 patients (57.7%) had died. Median OS was 2.6 years. Survival at 1, 3, and 5 years was 65.2%, 48.5%, and 38%, respectively. Conclusions: Radiation achieves high metastasis control rates for lung and mediastinal metastases from RCC, potentially delaying the need for systemic therapy.

AbstractObjectivesPrevious studies noted discordance of programmed death‐1 (PD‐1) and one of its ligands (PD‐L1) across patient‐matched primary and metastatic clear cell renal cell carcinoma (ccRCC). There are inconsistencies if the primary or metastatic tumor has higher expression, and whether metastatic tumor expression is associated with patient outcome. Thus, we examined PD‐1 and PD‐L1 in patient‐matched tumors using a large number of ccRCC patients with long follow‐up.Materials and MethodsWe analyzed PD‐1 and PD‐L1 using immunohistochemistry in patient‐matched primary and metastatic tumors from 110 ccRCC patients. Concordance was assessed among longitudinal metastatic tumors, as well as across patient‐matched primary and metastatic tumors. Cox proportional hazards regression was used to evaluate the associations of metastatic tumor expression with cancer‐specific survival.ResultsWe observed inter‐metastatic tumor heterogeneity of PD‐1 in 25 (69%) of the 36 patients and of PD‐L1 in seven (19%) patients. Concordance between patient‐matched primary and metastatic tumors was 73% (Kappa = 0.16, 95% CI: −0.003‐0.32). Similarly, concordance of PD‐L1 between metastatic and patient‐matched primary tumors was 78% (Kappa = 0.27, 95% CI: 0.09‐0.46). Both markers demonstrated higher expression in primary vs metastatic tumors. Metastatic tumor expression of PD‐1 was significantly associated with metastatic location (P < .0001) and ccRCC‐specific survival (HR = 2.15, 95% CI: 1.06‐4.36, P = .035).ConclusionsThe expression of PD‐1 and PD‐L1 is discordant across patient‐matched ccRCC tumors, with higher expression in primary tumors. Higher PD‐1 expression was associated with metastatic location and lower cancer‐specific survival. If validated, these results highlight the importance of evaluating these biomarkers in metastatic tissue specifically.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non–clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.

e23078 Background: There are limited patient (pt) reported outcome data regarding CDDP neurotoxicity. Methods: CDDP-induced peripheral neuropathy was evaluated in pts with testicular cancer planning to receive CDDP (20 mg/m2/d for 5 days) for ≥ 3 cycles. Neurotoxicity was assessed with the EORTC QLQ-CIPN20 tool before each CDDP cycle and every 2-4 months after, out to 18 months. We compared these data to our studies evaluating pts receiving doxorubicin/cyclophosphamide (AC), paclitaxel and oxaliplatin. The total score of the EORTC QLQ-CIPN20, each of the three subscale scores and each individual item was computed following the standard scoring algorithm and converted to a 0-100 scale. Descriptive statistics and graphical plots were utilized. Results: 54 pts receiving CDDP (mean age 33 years) and 18 pts receiving AC were evaluated. Following completion of CDDP, neuropathy symptoms (sensory neuropathy score and numbness/tingling in toes/feet) worsened for about 6 months (consistent with the so-called “coasting phenomena”), similar to what had previously been seen with oxaliplatin (but different than what had been seen with paclitaxel). For CDDP pts, during therapy, numbness and tingling in fingers/hands were more prominent, than the same symptoms in the toes/feet. After therapy was completed, numbness, and tingling became more prominent in toes/feet, but improved in the fingers/hands. After stopping therapy, shooting/burning pain did not worsen in upper or lower extremities. During therapy, CDDP pts had less problems than had previously been seen with oxaliplatin or paclitaxel, maybe because of the younger ages of the CDDP pts. With AC, all of the CIPN-20 sensory neuropathy scores were better than was seen in the pts receiving CDDP and also in pts receiving paclitaxel and oxaliplatin in previous evaluations. Conclusions: CDDP-induced neuropathy is more similar to oxaliplatin-induced neuropathy than paclitaxel-induced neuropathy. AC chemotherapy pts do not have substantial changes in CIPN 20 scores, consistent with the CIPN 20 instrument being a measure of chemotherapy-induced neuropathy, as opposed to more general chemotherapy-induced toxicities. Clinical trial information: NCT02677727.

e16559 Background: ARVs that develop early during treatment with abiraterone acetate/ prednisone (AA/P) may play a role in treatment resistance. We evaluated metastatic site and whole blood mRNA expression of full-length AR (AR-FL) and ARVs to characterize treatment-emergent ARVs (TE-ARVs) from men with mCRPC pre- and post- 12 weeks of AA/P collected in a prospective clinical trial (NCT#01953640). Methods: RNAseq performed on paired metastatic site biopsy (n = 40) and whole blood (n = 25) passed quality control. Reads were aligned to the GRCh38 reference genome with the spliced-alignment TopHat2 package. AR-FL or ARVs were detected if ≥ 2 splice reads aligned to unique splice junctions for AR-FL, AR-8, AR-45, AR-23, AR-V3, AR-V5V6, AR-V7, AR-V8, AR-V9, AR-V10, AR-V12, AR-V13, and AR-V14, and normalized to splice reads per million (SRPM). Cox proportional hazard regression analysis was performed on AR-FL and AR-Vs with ≥1 SRPM for association with time to treatment change (TTTC). Results: In metastatic site biopsies post-AA/P, the average number of splice reads was 27,376,541 (range 7,753,998 to 62,456,773). The median number of ARVs detected was 2 (range 0-8), with a total of total of 110 ARVs identified (Table). Dynamic shifts in ARV profiles were observed post-AAP, with 41 TE-ARVs identified in 17 unique patients. The most common TE-ARV was AR-8 (n = 8), followed by AR-45 (n = 5), AR-23 (n = 5), and AR-V7 (n = 4). The presence of AR-V7 post-AAP was adversely associated with TTTC (hazard ratio 2.46, p = 0.013). The identification of early TE- ARV was not associated with TTTC. In whole blood samples, post-AA/P detection of AR-FL was low (n = 3) and no ARVs were detected. Conclusions: No specific patterns were observed in ARV profiles obtained in the metastatic biopsies after 12 weeks of treatment with AA/P. Clinical trial information: 01953640. [Table: see text]

5063 Background: The systemic therapies available to patients with metastatic prostate cancer (mPC) have improved dramatically over the past decade. Prior to 2010, the only agents with a proven survival benefit for patients with metastatic disease were androgen deprivation therapy and docetaxel. Since then, five new agents have been FDA approved and have proven survival benefit in phase III trials. Anecdotal experience suggests that the increased available lines of therapy have changed the profile of mPC to include a higher prevalence of visceral metastases. Methods: A retrospective review of 474 patients with prostate cancer who died in 2009 and in 2016 was performed. Patients with metastatic disease who had imaging within 6 months of death were included. A total of 164 patients were eligible for analysis. Results: Mean age at death overall was 77.4 years (SD 9.5) and did not differ signifiantly by cohort. Overall rates of visceral and distant metastases to include lung, liver, adrenal, brain, renal, spleen, and thyroid, were higher in patients who died in 2016 as compared to those who died in 2009 (40.0% and 26.1%, respectively, p = 0.07). Lung metastases were more prevalent in patients who died in 2016 versus in 2009 at 26.3% and 13.0%, respectively (p = 0.05). Patients who died in 2009 received a median of 3 (range 1-10) systemic treatments versus 4 (range 0-13) in those who died in 2016 (p = 0.005). Forty-four percent of patients who died in 2016 used five or more lines of systemic treatments compared to 26.1% of patients in 2009. Conclusions: The emergence of new systemic therapies for mPC is changing the natural history of the disease. Forty percent of patients now develop visceral metastases compared to 26% in the past. These changes will drive the need for new treatment approaches targeting visceral metastases. [Table: see text]

4563 Background: We previously reported no difference in favorable response rate (FRR) or PFS for TIP vs BEP. Here we present results of a pre-planned analysis of biomarkers of outcome. Methods: HCG and AFP were drawn on days 1 and 15 of each cycle and rates of decline classified as satisfactory [S] or unsatisfactory [US] by MSK (Motzer JCO 2007) and GETUG (Fizazi Lancet Oncol 2014) methods. IHC for ERCC1, RAD51, PARP1, HER-2, and p-AKT was performed on pre-treatment tumor samples. An H-score (0 – 300) was calculated for each stain (H = stain intensity [0 – 3] x % positive cells [0-100]). H-score and marker decline category were correlated with FRR (PR + CR) and PFS. Patients (pts) who received disease-stabilizing chemotherapy were excluded from marker analyses. Results: Of 91 pts, 80 did not receive disease-stabilizing treatment with 79 having sufficient marker values for analysis by the MSK method and 75 by GETUG. By MSK, 49 had S decline vs 30 US; by GETUG, 34 S vs 41 US. FRR and PFS were improved for pts with S vs US decline by both methods and remained significant by the MSK method when stratified by IGCCCG group (Table). IHC (n=77) quality was adequate in 71 to 73 pts (varied by stain) and was positive (H >0) for PARP in 68/73, ERCC1 in 54/71, RAD51 in 54/73, p-AKT in 5/72, and HER2 in 4/72. Only PARP1 was associated with outcome with worse PFS for the lowest expression tertile (H < 180; p=0.013). Conclusions: PARP1 expression and tumor marker decline rates, particularly by MSK method, were significantly associated with outcome to initial chemotherapy in int/poor risk GCT. Future trials incorporating marker decline into treatment allocation and validating the prognostic effect of PARP1 expression are warranted. Clinical trial information: NCT01873326. [Table: see text]

4502 Background: Patients with no evidence of disease (NED) after metastasectomy for metastatic renal cell carcinoma (mRCC) are at high risk of recurrence, but no systemic therapy has been shown to benefit this population. Pazopanib is an inhibitor of VEGFR and other kinases that improves progression-free survival in patients with measurable RCC metastatic disease. We performed a randomized, double-blind, placebo-controlled multicenter study to test the hypothesis that pazopanib would improve disease-free survival in patients with mRCC rendered NED after metastasectomy Methods: Patients with NED following metastasectomy were randomized 1:1 to receive pazopanib starting at 800 mg daily vs. placebo for 52 weeks. Patients were stratified by 1 vs. > 1 site of resected disease, and by disease-free interval ≤ vs. > 1 year. Clinical assessment for toxicity and patient-reported outcomes were performed every 4 weeks, and restaging scans every 12 weeks. The study was designed to observe a 42% improvement in disease-free survival (DFS) from 25% to 45% at 3 years. Results: From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events had been observed (92% information). The median follow-up from randomization was 30 months (range 0.4 – 66.5 months). The study did not meet the primary endpoint: hazard ratio (95% CI) for DFS was 0.85 (0.55, 1.31) p= 0.47 in favor of pazopanib. At the time of unblinding, 22/129 (17%) of subjects had died. The HR for overall survival (OS) was 2.65 (1.02, 6.9) in favor of placebo ( p= 0.05). Patient-reported outcomes and laboratory correlates will be reported separately. Conclusions: 52 weeks of pazopanib did not improve DFS compared to blinded placebo in patients with mRCC who were NED after metastasectomy. There was a trend toward worse overall survival with pazopanib. Clinical trial information: NCT01575548.