At the first interim analysis of the phase 3 KEYNOTE-426 trial, first-line pembrolizumab plus axitinib showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) over sunitinib for advanced renal cell carcinoma (RCC). To assess long-term durability of clinical outcomes and elucidate predictive biomarkers for RCC, we performed efficacy and prespecified exploratory biomarker analyses from KEYNOTE-426 with ≥5 years of follow-up. Pembrolizumab plus axitinib showed sustained benefits in OS (hazard ratio: 0.84; 95% confidence interval: 0.71–0.99), PFS (hazard ratio: 0.69; 95% confidence interval: 0.59–0.81) and ORR (60.6% versus 39.6%) compared to sunitinib. An 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP) was positively associated with OS ( P = 0.002), PFS ( P < 0.0001) and ORR ( P < 0.0001) within the pembrolizumab plus axitinib arm. An angiogenesis signature was positively associated with OS ( P = 0.004) within the pembrolizumab plus axitinib arm and with OS ( P < 0.0001), PFS ( P < 0.001) and ORR ( P = 0.002) within the sunitinib arm. Across arms, programmed cell death ligand 1 combined positive score was only associated (negatively) with OS within the sunitinib arm ( P = 0.025). Additionally, PBRM1 (polybromo-1) mutation had a positive association with ORR ( P = 0.002) within the pembrolizumab plus axitinib arm. Within the sunitinib arm, OS was positively associated with VHL (von Hippel–Lindau tumor suppressor gene) ( P = 0.040) and PBRM1 ( P = 0.010) mutations and was negatively associated with BAP1 ( BRCA1- associated protein 1) mutation ( P = 0.019). Results showed a sustained clinical benefit with pembrolizumab plus axitinib over sunitinib and provide valuable information on biomarkers for immunotherapy-based treatment combinations in advanced RCC. Prospective clinical investigations are needed for biomarker-directed treatment for advanced RCC. ClinicalTrials.gov identifier: NCT02853331 .

536 Background: Some patients with primary renal cell carcinoma (RCC) are not candidates for surgery or nephron-sparing interventions due to various factors, such as the presence of a functional single kidney with a central, high-complexity tumor. This study aimed to evaluate whether a combination of nivolumab and ipilimumab could eliminate the primary tumor in patients with T1aN0M0 RCC. Methods: This prospective, multicenter, phase 2 pilot study enrolled patients with biopsy-confirmed clear-cell RCC (cT1a) ≤4 cm, no metastases, and who were ineligible for surgery or nephron-sparing procedures. Patients were treated with ipilimumab (1 mg/kg) every 3 weeks for four doses, alongside nivolumab (240 mg) every 2 weeks for eight doses. The primary endpoint was the complete response rate. Simon's two-stage design was used, testing the null hypothesis of a true complete response rate of 11%. A type I error rate of 0.05 and a power of 0.9 were set, with the null hypothesis rejected if 3 or more responses were observed in 8 patients. Results: From February 2020 to June 2021, 8 patients were enrolled, with a median age of 77.9 years (range 73–89). The cohort was entirely Caucasian, predominantly male (75%), and 62.5% had centrally located tumors. Six patients had moderate to severe comorbidities. All patients completed the immunotherapy without experiencing grade ≥2 adverse events. After a median follow-up of 37.4 months (95% CI 31.7–44.5), no complete responses were observed. However, partial responses were seen in 4 patients (50%), with continued tumor reduction after therapy. The median tumor size decreased from 3.11 cm (range 2.2–3.9) to 1.89 cm (range 1.1–4.0). Tumor shrinkage was observed in 6 patients (75%), while 1 patient experienced a slight tumor enlargement (+0.5 cm, +13%) after 9 months. The 3-year progression-free survival rate was 100%. Data on 5-year overall survival will be reported later. Conclusions: Although complete tumor regression was not achieved, immunotherapy with nivolumab and ipilimumab led to significant and durable tumor shrinkage in two-thirds of T1aN0M0 RCC patients, with minimal toxicity, making it a viable option for patients with significant comorbidities. Further data on long-term survival are awaited. Clinical trial information: NCT04134182 .

Outcomes from chemotherapy initiation in maintenance-eligible patients with locally advanced urothelial carcinoma (la/mUC) are of interest given new/emerging upfront immunotherapy-based treatment options. This exploratory analysis of KEYNOTE-361 by retrospective eligibility for maintenance therapy suggests that a majority of patients with untreated la/mUC who received chemotherapy alone may have been considered maintenance eligible; these patients had favorable survival outcomes relative to those considered maintenance ineligible. Introduction: The phase 3 KEYNOTE-361 trial of first-line pembrolizumab with or without chemotherapy versus chemotherapy alone in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) completed enrollment before the approval of postchemotherapy maintenance avelumab for patients without progressive disease. This post hoc analysis evaluated the outcomes of patients who received chemotherapy alone in KEYNOTE-361 by retrospective eligibility for subsequent maintenance therapy. Patients and Methods: Patients in the chemotherapy alone arm were retrospectively categorized as maintenance eligible (received >= 4 cycles of chemotherapy and did not die or experience disease progression within 10 weeks of chemotherapy completion), maintenance ineligible (received < 4 cycles of chemotherapy or had progressive disease or died within 0-10 weeks after completion of >= 4 cycles of chemotherapy), and indeterminate eligibility for maintenance therapy (if neither maintenance eligible or ineligible). End points included progression-free survival per Response Evaluation Cr iter ia in Solid Tumors version 1.1 by blinded independent central review and overall survival from randomization (start of chemotherapy). Results: Median follow-up was 31.7 months (range, 22.0-42.3). Among 342 patients who received chemotherapy alone, 172 (50.3%) were maintenance eligible, 108 (31.6%) were maintenance ineligible, and 62 (18.1%) had indeterminate eligibility for maintenance therapy. The median progression-free survival was 9.0 months (95% CI 8.4-10.4) in maintenance-eligible patients, 5.1 months (4.2- 6.0) in maintenance-ineligible patients, and 2.3 months (1.9-3.8) in the indeterminate group; median overall survival was 23.3 months (95% CI 19.4-26.1), 10.2 months (9.1-11.6), and 5.5 months (3.7-8.5), respectively. Conclusion: This post hoc analysis suggests that a majority of patients with untreated la/mUC who initiated chemotherapy in a clinical trial may have been considered eligible for maintenance therapy and had favorable survival outcomes compared with those considered maintenance ineligible.

BACKGROUND AND OBJECTIVE:In the phase 3 KEYNOTE-921 study, the combination of pembrolizumab with docetaxel did not improve efficacy outcomes significantly in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) after next-generation hormonal agents (NHAs). This analysis of KEYNOTE-921 assessed patient-reported outcomes (PROs) associated with pembrolizumab plus chemotherapy versus chemotherapy alone. METHODS:Eligible patients were assigned randomly in a 1:1 ratio to receive pembrolizumab or placebo, both with docetaxel and prednisone. The time to pain progression measured by the Brief Pain Inventory-Short Form was a secondary end point. Health-related quality of life (HRQoL) scores, including disease-related symptoms, assessed by the Functional Assessment of Cancer Therapy-Prostate and EuroQol five-dimension five-level were prespecified exploratory end points. KEY FINDINGS AND LIMITATIONS:The PRO analysis set comprised 1028 patients; the median follow-up was 22.7 mo from baseline until database cutoff (June 20, 2022). The median time to pain progression was 21.1 mo (95% confidence interval [CI] 13.7 to not reached [NR]) and NR (95% CI 13.8-NR) in the pembrolizumab and placebo arms, respectively (hazard ratio 1.05; 95% CI 0.77-1.43). Changes from baseline in PRO end points were similar between treatment arms and remained generally stable throughout the study. Limitations include a lack of formal hypothesis testing to detect between-arm differences in PROs. CONCLUSIONS AND CLINICAL IMPLICATIONS:No meaningful differences in PROs were observed in patients with mCRPC treated with pembrolizumab plus chemotherapy versus chemotherapy alone. These findings indicate that adding an immune checkpoint inhibitor to chemotherapy does not positively or negatively impact HRQol in patients with mCRPC previously treated with NHAs.

PURPOSE:The standard of care for metastatic castration-resistant prostate cancer (mCRPC) after second-generation androgen receptor pathway inhibitor (ARPI) therapy is still docetaxel. The randomized, double-blind, phase III KEYNOTE-921 trial (Clinicaltrials.gov identifier: NCT03834506) evaluated the efficacy and safety of pembrolizumab or placebo plus docetaxel for previously treated mCRPC. METHODS:Adults with mCRPC who progressed after androgen-deprivation therapy and one ARPI were randomly assigned 1:1 to pembrolizumab or placebo plus docetaxel with concomitant prednisone. Dual primary end points were radiographic progression-free survival (rPFS) by blinded independent central review per Prostate Cancer Working Group 3-modified RECIST 1.1 and overall survival (OS). Safety was a secondary end point. RESULTS:Between May 30, 2019, and June 17, 2021, 515 participants were randomly assigned to pembrolizumab plus docetaxel and 515 to placebo plus docetaxel. Median time from random assignment to data cutoff date (June 20, 2022) at final analysis (FA) was 22.7 months (range, 12.1-36.7). At first interim analysis (data cutoff date: September 27, 2021), median rPFS was 8.6 months (95% CI, 8.3 to 10.2) with pembrolizumab plus docetaxel versus 8.3 months (95% CI, 8.2 to 8.5) with placebo plus docetaxel (hazard ratio [HR], 0.85 [95% CI, 0.71 to 1.01]; P = .03). At FA, median OS was 19.6 months (95% CI, 18.2 to 20.9) versus 19.0 months (95% CI, 17.9 to 20.9), respectively (HR, 0.92 [95% CI, 0.78 to 1.09]; P = .17). Grade ≥3 treatment-related adverse events occurred in 43.2% of participants who received pembrolizumab plus docetaxel and 36.6% of participants who received placebo plus docetaxel. Two and seven participants, respectively, died due to a treatment-related adverse event. Pneumonitis was the most common immune-mediated adverse event (7.0% v 3.1%). CONCLUSION:The addition of pembrolizumab to docetaxel did not significantly improve efficacy outcomes for participants with previously treated mCRPC. The current standard of care remains unchanged.

4505 Background: P + A improved OS, PFS, and ORR over S in 1L advanced RCC in KEYNOTE-426 (NCT02853331).Here, we present exploratory biomarker results including RNAseq, WES, and PD-L1. Methods: Patients (pts) with treatment-naive advanced RCC were randomly assigned 1:1 to P + A or S. Association between T-cell–inflamed gene signature (TcellinfGEP), angiogenesis gene signature (RNAseq), and PD-L1 CPS (22C3 IHC) with clinical outcomes were tested at prespecified α=0.05. Other RNA signatures (Cristescu et al. Clin Cancer Res. 2022. 2022;28:1680) and molecular subtypes, based on clustering identified from IMmotion151 (Motzer et al. Cancer Cell. 2020;38:803), were tested at prespecified α = 0.10 after multiplicity adjustment. DNA mutations ( VHL, PBRM1, SETD2, and BAP1) by WES were tested at prespecified α = 0.10 after multiplicity adjustment. Results: Of 861 pts, 369 (P + A) and 361 (S) had archival samples for RNAseq; 347 (P + A) and 351 (S) had WES samples. PD-L1 CPS was negatively associated with OS ( P=0.013) for S. There was a strong positive association of TcellinfGEP with OS ( P=0.003), PFS ( P<0.0001), and ORR ( P<0.0001) for P + A. Angiogenesis was positively associated with OS ( P=0.013) for P + A; there was a strong positive association with OS ( P<0.0001), PFS ( P<0.001), and ORR ( P=0.002) for S. For other RNA signatures, positive association with mMDSC was found for PFS ( P=0.018) and ORR ( P=0.093) with P + A. For S, positive association was found with hypoxia (OS, P=0.034; ORR, P=0.071) and negative associations with MYC (OS, P<0.001; PFS, P=0.012) and proliferation (OS, P=0.002). Across all molecular clusters, ORR favored P + A over S, with the highest P + A ORR in the immune/proliferative cluster (Table). By WES, PBRM1 mutation had positive association with ORR ( P=0.004) and PFS ( P=0.079) for P + A. For S, positive associations were observed with OS for VHL ( P=0.073) and PBRM1 ( P=0.001) mutations and a negative one observed for BAP1 mutation ( P=0.046). P + A improved ORR over S regardless of mutational status. Conclusions: There was a strong relationship of TcellinfGEP with clinical outcomes with P + A. Angiogenesis was positively associated with outcomes with S and only with OS with P + A. Further understanding the role of the immune microenvironment in combination therapy will be critical to advance treatment strategies. Clinical trial information: NCT02853331 . [Table: see text]

Abstract Background Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. Methods KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. Results One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2–14.3) and 10.3 months (2.7–13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2–44.1] and sunitinib/pazopanib (29.2% [18.6–41.8]). Grade 3–5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. Conclusions ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. Clinical trial registration ClinicalTrials.gov; NCT03260894 .

Therapeutic landscape of several genitourinary malignancies has been revolutionized by the development of immune checkpoint inhibitors; however, the utility of immunotherapies in prostate cancer has been limited, partly due to the immunologically “cold” tumor microenvironment of prostate cancer. As of today, pembrolizumab is the only immune checkpoint inhibitor approved for treatment of metastatic castration-resistant prostate cancer (mCRPC) in a select group of patients with high microsatellite instability, deficient mismatch repair, or high tumor mutational burden. Currently, several combinations with immune checkpoint inhibitors involving radioligands, radiotherapy, PARP inhibitors, interleukin inhibitors, and cancer vaccines are being explored for potential synergistic effect. Furthermore, B7-H3 is an alternative checkpoint that may hold promise in treatment of mCRPC. This review aims to summarize previous monotherapy and combination therapy trials of immune checkpoint inhibitors as well as novel immunotherapy combinations and treatment targets in mCRPC.

BACKGROUND: Niraparib is a highly selective poly (adenosine diphosphateribose) polymerase-1 and poly (adenosine diphosphate-ribose) polymerase-2 inhibitor indicated for select patients with ovarian, fallopian tube, and primary peritoneal cancer. The phase 2 GALAHAD trial ( NCT02854436) demonstrated that niraparib monotherapy is tolerable and efficacious in patients with metastatic castration- resistant prostate cancer (mCRPC) and homologous recombination repair ( HRR) gene alterations, particularly those with breast cancer gene ( BRCA) alterations who had progressed on prior androgen signaling inhibitor therapy and taxanebased chemotherapy. OBJECTIVE: To report the prespecified patient-reported outcomes analysis from GALAHAD. METHODS: Eligible patients with alterations to BRCA1 and/or BRCA2 (BRCA cohort) and with pathogenic alterations in other HRR genes (other HRR cohort) were enrolled and received niraparib 300 mg once daily. Patient-reported outcome instruments included the Functional Assessment of Cancer Therapy- Prostate and the Brief Pain Inventory-Short Form. Changes from baseline were compared using a mixed-effect model for repeated measures. RESULTS: On average, health-related quality of life (HRQoL) improved in the BRCA cohort by cycle 3 (mean change = 6.03; 95% CI =2.76-9.29) and was maintained above baseline until cycle 10 (mean change = 2.84; 95% CI= -1.95 to 7.63), whereas the other HRR cohort showed no early change in HRQoL from baseline (mean change =-0.07; 95% CI =-4.69 to 4.55) and declined by cycle 10 (mean change = -5.10; 95% CI= -15.3 to 5.06). Median time to deterioration in pain intensity and pain interference could not be estimated in either cohort. CONCLUSIONS: Patients with advanced mCRPC and BRCA alterations treated with niraparib experienced more meaningful improvement in overall HRQoL, pain intensity, and pain interference compared with those with other HRR alterations. In this population of castrate, heavily pretreated patients with mCRPC and HRR alterations, stabilization, and improvement in HRQoL may be relevant to consider when making treatment decisions.

19 Background: Docetaxel is a treatment option following disease progression on a next-generation hormonal agent (NHA) for patients with mCRPC, but there is an urgent need for more efficacious treatments. The randomized, double-blind, phase 3 KEYNOTE-921 study (NCT03834506) evaluated the efficacy and safety of pembrolizumab + docetaxel vs placebo + docetaxel for participants (pts) with mCRPC who had received prior NHA therapy. Methods: Eligible pts were ≥18 years old, had mCRPC that progressed on androgen deprivation therapy, had received 1 prior NHA, and had an ECOG performance status of 0 or 1. Pts were randomized 1:1 to receive 200 mg pembrolizumab Q3W or placebo for ≤35 cycles (~2 years) in combination with 75 mg/m2 docetaxel Q3W for ≤10 cycles and 5 mg prednisone BID. The dual primary endpoints were radiographic progression-free survival (rPFS; tested at first interim analysis) per PCWG-modified RECIST 1.1 by blinded independent central review and overall survival (OS; tested at final analysis). The key secondary endpoint was time to initiation of the first subsequent anticancer therapy (TFST; at first interim analysis). Safety was one of the secondary endpoints. Results: Between May 30, 2019 and June 17, 2021, 1030 pts were randomized to receive pembrolizumab + docetaxel (n=515) or placebo + docetaxel (n=515). The median (range) time from randomization to data cutoff date of June 20, 2022 at final analysis was 22.7 mo (12.1−36.7). Baseline characteristics were generally balanced between arms; approximately half of pts in each arm had received prior abiraterone. Pts in the pembrolizumab + docetaxel arm received a median (range) of 12 (1–35) cycles of pembrolizumab and 9 (1–12) cycles of docetaxel; pts in the placebo + docetaxel arm received a median (range) of 12 (1–35) cycles of placebo and 9 (1–10) cycles of docetaxel. The dual primary endpoints of rPFS (median 8.6 mo with pembrolizumab + docetaxel vs 8.3 mo with placebo + docetaxel; HR 0.85, 95% CI 0.71−1.01; P=0.0335) and OS (median 19.6 mo vs 19.0 mo; HR 0.92, 95% CI 0.78−1.09; P=0.1677) were not met. Median TFST was 10.7 mo vs 10.4 mo, respectively (HR 0.86, 95% CI 0.74−1.01). Treatment-related AEs occurred in 94.6% (grade ≥3 in 43.2%) and 94.9% (grade ≥3 in 36.6%) of pts with pembrolizumab + docetaxel vs placebo + docetaxel. 2 treatment-related deaths with pembrolizumab + docetaxel and 7 with placebo + docetaxel were reported. Immune-mediated AEs and infusion reactions occurred in 23.3% (grade ≥3 in 6.2%) and 12.3% (grade ≥3 in 1.2%) of pts with pembrolizumab + docetaxel vs placebo + docetaxel, most commonly pneumonitis (7.0% vs 3.1%) and hypothyroidism (6.4% vs 3.3%). Conclusions: The addition of pembrolizumab to docetaxel did not significantly improve rPFS or OS for pts with mCRPC and did not result in a notable increase in treatment-related AEs. Clinical trial information: NCT03834506 .

PURPOSEThere is an unmet need for therapeutic options that prolong survival for patients with heavily pretreated, metastatic castration-resistant prostate cancer (mCRPC). The phase III, open-label KEYLYNK-010 study evaluated pembrolizumab plus olaparib versus a next-generation hormonal agent (NHA) for biomarker-unselected, previously treated mCRPC.METHODSEligible participants had mCRPC that progressed on or after abiraterone or enzalutamide (but not both) and docetaxel. Participants were randomly assigned (2:1) to pembrolizumab plus olaparib or NHA (abiraterone or enzalutamide). The dual primary end points were radiographic progression-free survival (rPFS) by blinded independent central review per Prostate Cancer Working Group-modified RECIST 1.1 and overall survival (OS). Time to first subsequent therapy (TFST) was a key secondary end point. Safety and objective response rate (ORR) were secondary end points.RESULTSBetween May 30, 2019, and July 16, 2021, 529 participants were randomly assigned to pembrolizumab plus olaparib and 264 to NHA. At final rPFS analysis, median rPFS was 4.4 months (95% CI, 4.2 to 6.0) with pembrolizumab plus olaparib and 4.2 months (95% CI, 4.0 to 6.1) with NHA (hazard ratio [HR], 1.02 [95% CI, 0.82 to 1.25]; P = .55). At final OS analysis, median OS was 15.8 months (95% CI, 14.6 to 17.0) and 14.6 months (95% CI, 12.6 to 17.3), respectively (HR, 0.94 [95% CI, 0.77 to 1.14]; P = .26). At final TFST analysis, median TFST was 7.2 months (95% CI, 6.7 to 8.1) versus 5.7 months (95% CI, 5.0 to 7.1), respectively (HR, 0.86 [95% CI, 0.71 to 1.03]). ORR was higher with pembrolizumab plus olaparib versus NHA (16.8% v 5.9%). Grade >= 3 treatment-related adverse events occurred in 34.6% and 9.0% of participants, respectively.CONCLUSIONPembrolizumab plus olaparib did not significantly improve rPFS or OS versus NHA in participants with biomarker-unselected, heavily pretreated mCRPC. The study was stopped for futility. No new safety signals occurred.

Previous analyses of KEYNOTE-426, an open-label, phase 3 randomized study, showed superior efficacy of first-line pembrolizumab plus axitinib to sunitinib in advanced clear cell renal cell carcinoma (ccRCC). We report results of the final protocol-prespecified analysis of KEYNOTE-426. Patients received pembrolizumab 200 mg intravenously every 3 wk plus axitinib 5 mg orally twice daily or sunitinib 50 mg orally once daily (4 wk per 6-wk cycle). The dual primary endpoints were overall survival (OS) and progression-free survival (PFS) as per RECIST v1.1 by a blinded independent central review. The secondary endpoints included objective response rate (ORR) and duration of response (DOR). The median study follow-up was 43 (range, 36-51) mo. Benefit with pembrolizumab plus axitinib versus sunitinib was maintained for OS (hazard ratio [HR], 0.73 [95% confidence interval {CI}, 0.60-0.88]), PFS (HR, 0.68 [95% CI, 0.58-0.80]), and ORR (60% vs 40%). The median DOR was 24 (range, 1.4+ to 43+) versus 15 (range, 2.3-43+) mo in the pembrolizumab plus axitinib versus the sunitinib arm. No new safety signals emerged. These results support pembrolizumab plus axitinib as a standard of care for patients with previously untreated advanced ccRCC. PATIENT SUMMARY: Extended results of KEYNOTE-426 support pembrolizumab plus axitinib as the standard of care for advanced clear cell renal cell carcinoma.

129 Background: The double-blind, phase 3, randomized KEYNOTE-921 trial (NCT03834506) showed that pembro + docetaxel did not significantly improve rPFS or OS for pts with mCRPC treated with prior next-generation hormonal agent (NHA) therapy. We present PROs for pembro + docetaxel vs placebo + docetaxel in KEYNOTE-921. Methods: Pts were randomly assigned 1:1 to receive pembro 200 mg or placebo IV Q3W (≤35 cycles) + docetaxel 75 mg/m2 IV Q3W (≤10 cycles) and prednisone 5 mg orally BID. PROs were evaluated in pts who received ≥1 dose of study treatment and had ≥1 PRO assessment. FACT-P and BPI-SF were administered at baseline, Q3W until wk 24, Q6W until wk 72, then Q12W for ≤2 y. A prespecified secondary end point was time to pain progression (TTPP) based on BPI-SF. Prespecified exploratory end points included least squares mean (LSM) change from baseline to wk 27 for FACT-P total and subscale scores (FACT-G total, TOI, FAPSI-6, FWB, PWB, and PCS) and wk 24 for BPI-SF scores (pain interference, pain severity, and worst pain), and time to deterioration (TTD) and overall improvement rate in FACT-P total and subscale scores. Differences were evaluated using 2-sided nominal P values not controlled for multiplicity. Results: Of 1030 pts enrolled, the PRO analysis population included 1028 (n = 514 in each arm). At the prespecified final analysis, median time from randomization to data cutoff of June 20, 2022, was 22.7 mo (range, 12.1-36.7). Completion rates for FACT-P and BPI-SF were >78% at baseline, >65% for FACT-P at wk 27, and >63% for BPI-SF at wk 24. Median TTPP was 21.1 mo (95% CI, 13.7-NR) for pembro + docetaxel vs NR (95% CI, 13.8-NR) for placebo + docetaxel (HR, 1.05 [95% CI, 0.77-1.43]). No LSM differences were observed in FACT-P total scores with pembro + docetaxel (–5.31 [95% CI, –7.02 to –3.61]) vs placebo + docetaxel (–3.89 [95% CI, –5.59 to –2.19]) or BPI-SF scores. Median TTD in FACT-P total scores was 21.8 mo (95% CI, 20.0-NR) for pembro + docetaxel and NR (95% CI, 11.1-NR) for placebo + docetaxel (HR, 1.09 [95% CI, 0.88-1.35]). No differences were observed for TTD in FACT-G total, TOI, FAPSI-6, FWB, PWB, and PCS scores between groups. A numerically lower proportion of pts receiving pembro + docetaxel (39.9%) had improved + stable FACT-P total scores compared with placebo + docetaxel (45.3%). FACT-P and BPI-SF scores were generally maintained across all evaluated time points up to wk 81. Conclusions: HRQoL and disease-related symptom scores at all analyzed time points, as well as TTD and TTPP, were similar between the 2 trial arms. These data suggest that pembro + docetaxel did not negatively impact QoL in pts with mCRPC treated with prior NHA. Clinical trial information: NCT03834506 . [Table: see text]

The phase 3 KEYNOTE-361 trial (NCT02853305) of 1L pembrolizumab + chemotherapy (chemo) or pembrolizumab vs chemo alone in pts with advanced UC completed enrollment prior to approval of PD-L1 maintenance therapy after 1L chemo. This post hoc exploratory analysis evaluated pts who received chemo by eligibility for post-chemo maintenance therapy. Pts who received chemo alone were retrospectively categorized as eligible (received ≥4 cycles of chemo and either did not have PD or died within 0-10 wk after completion of chemo or did have a PD or died >10 wk after completion of chemo) or ineligible (received ≥4 cycles of chemo and had a PD or died while on chemo or within 0-10 wk after completion of chemo) for post-chemo maintenance. Pts who received <4 cycles of chemo, were censored before end of chemo, or had nonevaluable or missing scans within 10 wk of chemo were excluded. Exploratory end points were PFS, landmark PFS (time from last non-PD assessment within 0-10 wk of chemo completion to PD per RECIST v1.1 by BICR), OS, and landmark OS (time from last non-PD assessment within 0-10 wk of chemo completion to death). Median follow-up was 31.7 mo (range, 22.0-42.3). Among 342 pts in the chemo arm, 172 (50.3%) were eligible for maintenance, 108 (31.6%) were ineligible, and 62 (18.1%) were excluded; 85/172 pts (49.4%) received subsequent anti–PD-1/L1 therapy. Results for pts eligible for post-chemo maintenance are reported (Table). For maintenance-ineligible pts, median (95% CI) PFS and OS were 5.1 mo (4.2-6.0) and 10.2 mo (9.1-11.6), respectively. This post hoc exploratory analysis demonstrates that pts who are eligible for post-chemo maintenance therapy have a favorable prognosis. About 50% of pts who initiated chemo on a clinical trial were considered eligible for maintenance therapy. To our knowledge, these are the first exploratory data describing outcomes of maintenance-eligible pts from the initiation of chemo.Table: 2373PMaintenance eligible n = 172PFS, median (95% CI%), mo9.0 (8.4-10.4)PFS rate at 12 mo, % (95% CI)35.1 (27.3-43.0)Landmark PFS, median (95% CI), mo4.1 (2.9-6.1)Landmark PFS rate at 12 mo, % (95% CI)25.2 (17.9-33.2)OS, median (95% CI, mo)23.3 (19.4-26.1)OS rate at 24 mo, % (95% CI)46.8 (39.2-54.1)Landmark OS, median (95% CI), mo18.8 (14.6-21.8)Landmark OS rate at 24 mo, % (95% CI)39.9 (32.2-47.5) Open table in a new tab

Background: Some patients with primary renal cell carcinoma (RCC) are unable to have surgery for different reasons (functional single kidney with a central, high-complexity RCC, high risk of nephrectomy and dialysis, patients with complex coagulation disorders, etc.). We hypothesize that combination of nivolumab and ipilimumab could eliminate the primary tumor in T1aN0M0 patients ineligible for surgical treatment. Methods: This is a prospective, multicenter, non-randomized phase 2 pilot study. Patients with biopsy-proven clear-cell RCC of ≤4 cm (cT1a), no evidence of any metastases, and unable to have surgery or other nephron-sparing interventions (ablation) or with preference to have no surgery or intervention for any reason received combination of ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, and nivolumab (240 mg intravenously) every 2 weeks during 16 weeks. The primary endpoint was complete response rate. Simon's two-stage design was used. The null hypothesis that the true complete response rate was 11% and was tested against a one-sided alternative. This design yields a type I error rate of 0.05 and power of 0.9 when the true complete response rate is 60% (alternative hypothesis). The null hypothesis should be rejected if 3 or more responses are observed in 8 patients. Results: Between February 2020 and June 2021, 8 patients were included. Median age was 77.9 years (range 73-89). Patients were Caucasian (100%), predominantly male (75%), 62.5% had centrally located RCC, 25% had ECOG PS 1, and 6 of 8 patients had moderate and severe comorbidities. Median follow-up was 12.7 months (95% CI 5.2-16.5). All patients received immunotherapy during 4 months without grade ≥2 adverse events. No complete responses were observed. Partial responses were found in 2 patients (25%). Median size of the primary tumor at RCC diagnosis and after immunotherapy was 3.11 cm (range 2.2-3.9) and 2.86 cm (range 1.5-4.0), respectively. Any shrinkage of the primary tumor was reported in 4 (50%) patients (change in median sum of diameters -18%). Only one patient had tumor enlargement (+0.5 cm (+13%) after 9 months. SBRT was used in this patient. All other patients are under active surveillance. Next secondary end-point of 3-year progression-free survival will be reported. Conclusions: The activity of immunotherapy against primary tumor was limited in patients with T1aN0M0 RCC ineligible for surgical treatment. Duration of stable disease will be studied with long-term follow-up of these patients. Treatment with nivolumab and ipilimumab was safe in patients with moderate and severe comorbidities. Citation Format: Ilya Tsimafeyeu, Maria Volkova, Rustem Gafanov, Igor Myslevtsev, Andrey Andrianov, Axel Bex. Primary tumor response in T1aN0M0 renal cell carcinoma patients ineligible for surgery and treated with nivolumab and ipilimumab: Results from phase 2 pilot study [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 CT106.