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Background Docetaxel has immunostimulatory effects that may promote an immunoresponsive prostate tumour microenvironment, providing a rationale for combination with nivolumab (programmed death-1 inhibitor) for metastatic castration-resistant prostate cancer (mCRPC). Methods In the non-randomised, multicohort, global phase II CheckMate 9KD trial, 84 patients with chemotherapy-naive mCRPC, ongoing androgen deprivation therapy and ≤2 prior novel hormonal therapies (NHTs) received nivolumab 360 mg and docetaxel 75 mg/m2 every 3 weeks with prednisone 5 mg twice daily (≤10 cycles) and then nivolumab 480 mg every 4 weeks (≤2 years). The co-primary end-points were objective response rate (ORR) and prostate-specific antigen response rate (PSA50-RR; ≥50% decrease from baseline). Results The confirmed ORR (95% confidence interval [CI]) was 40.0% (25.7–55.7), and the confirmed PSA50-RR (95% CI) was 46.9% (35.7–58.3). The median (95% CI) radiographic progression-free survival (rPFS) and overall survival (OS) were 9.0 (8.0–11.6) and 18.2 (14.6–20.7) months, respectively. In subpopulations with versus without prior NHT, the ORR was 38.7% versus 42.9%, the PSA50-RR was 39.6% versus 60.7%, the median rPFS was 8.5 versus 12.0 months and the median OS was 16.2 months versus not reached. Homologous recombination deficiency status or tumour mutational burden did not appear to impact efficacy. The most common any-grade and grade III–IV treatment-related adverse events were fatigue (39.3%) and neutropenia (16.7%), respectively. Three treatment-related deaths occurred (1 pneumonitis related to nivolumab; 2 pneumonias related to docetaxel). Conclusions Nivolumab plus docetaxel has clinical activity in patients with chemotherapy-naive mCRPC. Safety was consistent with the individual components. These results support further investigation in the ongoing phase III CheckMate 7DX trial. ClinicalTrials.gov registration NCT03338790.

Background Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long-term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC). Although most phase 3 clinical trials exclude patients with brain metastases, the ongoing, multicohort phase 3b/4 CheckMate 920 trial (ClincalTrials.gov identifier NCT02982954) evaluated the safety and efficacy of NIVO + IPI in a cohort that included patients with aRCC and brain metastases, as reported here. Methods Patients with previously untreated aRCC and asymptomatic brain metastases received NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × 4 followed by NIVO 480 mg every 4 weeks. The primary end point was the incidence of grade ≥3 immune-mediated adverse events (imAEs) within 100 days of the last dose of study drug. Key secondary end points were progression-free survival and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (both determined by the investigator). Exploratory end points included overall survival, among others. Results After a minimum follow-up of 24.5 months (N = 28), no grade 5 imAEs occurred. The most common grade 3 and 4 imAEs were diarrhea/colitis (n = 2; 7%) and hypophysitis, rash, hepatitis, and diabetes mellitus (n = 1 each; 4%). The objective response rate was 32% (95% CI, 14.9%-53.5%) with a median duration of response of 24.0 months; 4 of 8 responders remained without reported progression. Seven patients (25%) had intracranial progression. The median progression-free survival was 9.0 months (95% CI, 2.9-12.0 months), and the median overall survival was not reached (95% CI, 14.1 months to not estimable). Conclusions In patients who had previously untreated aRCC and brain metastases-a population with a high unmet medical need that often is underrepresented in clinical trials-the approved regimen of NIVO + IPI followed by NIVO showed encouraging antitumor activity and no new safety signals.

While immunotherapy with nivolumab is promising for patients with renal cell carcinoma (RCC), overactivation of the immune system can lead to serious side effects. Immune-related meningoencephalitis without a viral or microbial etiology is a rare complication that may occur in patients treated with checkpoint inhibitors (CPI). Herein, we report a 66-year-old man who underwent a partial nephrectomy which revealed a papillary RCC with clear cell component. Three years later, an abdomen and pelvic CT revealed metastatic lesions in the left psoas muscle and in the left 12th rib. The patient was treated with pazopanib which was discontinued after 2 weeks due to significant hepatic and renal toxicity. He subsequently started sunitinib. Two months later, a chest, abdomen, and pelvic CT demonstrated progressive metastatic RCC in the retroperitoneal mass of the left psoas muscle and paraspinal musculature as well as a left renal mass. The patient was treated with 7 cycles of the CPI nivolumab. He was subsequently hospitalized for 3 weeks after experiencing bilateral lower extremity weakness, lethargy, several falls, hyperthermia, confusion, and gait abnormalities. A CSF analysis demonstrated a lymphocyte pleocytosis with elevated protein and no bacterial or viral growth. The patient was treated with high-dose steroids after which his symptoms resolved. Chest, abdomen, and pelvic CT scans over the next 3 years revealed no evidence of metastatic disease, reflecting a progression-free survival of 40 months. We highlight the unique case of a patient with metastatic RCC who experienced immune-related meningoencephalitis following immunotherapy with nivolumab. Medical oncologists should be alert to the potential development of immune-related encephalitis in patients treated with nivolumab and should promptly diagnose and treat this concerning condition. The excellent oncologic outcome of this case emphasizes the need for continued aggressive measures for management of CNS toxicity resulting from CPI therapy.

Introduction Patients with muscle-invasive urothelial bladder cancer post neoadjuvant cisplatin-based chemotherapy with pathologic advanced disease (ypT3, ypT4, ypN+) at radical cystectomy have a significantly worse five-year overall survival. There is currently no preferred adjuvant therapy to reduce risk of cancer recurrence in this high-risk patient cohort and surveillance remains the standard-of-care. Case report We present a case series of two patients who received cisplatin-based neoadjuvant chemotherapy and had pathologic node-positive urothelial carcinoma at the time of radical cystectomy. Tumor next generation sequencing revealed high mutational burden in both patients and positive PD-L1 in one patient. Management and outcome: Patients were treated with adjuvant pembrolizumab and experienced long-term disease free intervals. Discussion Use of adjuvant checkpoint inhibitors in patients post neoadjuvant cisplatin-based chemotherapy with pathologic advanced disease at the time of radical cystectomy at high-risk of cancer recurrence sounds appealing. Careful patient selection based on tumor-specific genomic alterations may be key. Large trials addressing this question are ongoing.

Advanced prostate cancer is a continuum of states distinguished by the presence or absence of metastasis and sensitivity or resistance to androgen deprivation therapy (ADT). Therapeutic options for this disease continue to rapidly evolve, making it a challenge to apply results of clinical trial data to daily patient management. One question relevant to providers is whether molecular biomarkers predictive of response or resistance to therapies are available to guide clinical treatment decisions. Other salient topics include the timing of therapy initiation in patients with biochemical recurrence, treatment approach in low-volume versus high-volume metastatic castrate-sensitive prostate cancer, types of agents available beyond ADT, and timing of their use in men with nonmetastatic castrate-resistant prostate cancer as well as whether sequencing of therapies in metastatic castrate-resistant prostate cancer matters. Additionally, familiarity with emerging treatment strategies is important. This review addresses the gray areas and challenging questions in advanced prostate cancer management that frequently arise in clinical practice.

Renal cell carcinoma (RCC) is often metastatic at diagnosis. Conventional therapies such as chemotherapy, radiotherapy, and hormonal therapy have generally proven ineffective in the treatment of RCC. The abscopal effect, specifically, the ability of localized radiation to trigger systemic antitumor effects, has been reported to lead to regression of non-irradiated distant tumor lesions. Herein, we report 3 patients with non-metastatic clear cell RCC (CCRCC) who underwent a nephrectomy and experienced metachronous pulmonary/mediastinal metastases confirmed as CCRCC. No patients underwent radiation post-nephrectomy or pulmonary metastasectomy. The mean duration was 7.24 weeks from the last negative chest CT prior to the nephrectomy and 96.2 weeks post-nephrectomy. All patients achieved durable complete response by RECIST criteria, with a mean follow-up duration of 115 months. Our case series represents the largest in the literature of patients who underwent a nephrectomy for CCRCC with no pre-existing pulmonary/mediastinal metastatic disease confirmed by chest CT, did not undergo radiotherapy, and developed significantly delayed CCRCC pulmonary/mediastinal metastases. We highlight the spontaneous regression of delayed metastatic disease and the role of immune responses in curtailing the growth of pulmonary metastasis in CCRCC.

Background The presence of renal cell carcinoma (RCC) and hematologic malignancies (HM) in the same patient is rarely observed. Three primary findings have been described in these patients, including male gender and lymphoid malignancy predominance, and the HM are usually diagnosed before or simultaneously with the RCC. There is a lack of evidence about clinical outcomes in this setting. We report the common characteristics of 9 patients diagnosed with concurrent RCC and HM and their clinical course and response to treatment. Case summary Four (44%) patients were diagnosed with RCC prior to the HM, the diagnosis was simultaneous in 4 (44%) patients, and 1 (11%) patient was diagnosed with the HM prior to the RCC. No patients were treated with cytotoxic chemotherapy or radiation between the diagnosis of RCC and HM. Several unique features were seen in our case series, such as 3 simultaneous cancers in 1 (11%) patient, a splenectomy leading to remission of diffuse large B cell lymphoma without the use of chemotherapy in 1 (11%) patient, chemotherapy and rituximab for lymphoma resulting in a complete response in primary RCC in 1 (11%) patient, and immunotherapy providing an excellent response for primary renal leiomyosarcoma in 1 (11%) patient. Conclusion These findings highlight the potential role of immune system dysregulation in patients with the diagnosis of RCC and HM whereby the first malignancy predisposes to the second through an immunomodulatory effect. HM have the potential of being confused with lymph node metastasis from kidney cancer. Lymph node biopsy may be necessary at the time of initial diagnosis or in cases of mixed response to therapy. Long-term medical surveillance is warranted when a patient is diagnosed with RCC or HM. Clinicians should be aware of the higher prevalence of male gender and lymphoid malignancy with concurrent RCC and HM and that either of these conditions may be diagnosed first or they may be diagnosed simultaneously.

Background Clear cell adenocarcinoma of the urethra is a rare type of aggressive cancer with a poor prognosis. Clear cell carcinoma of the urethra represents less than 0.02% of all malignancies in women. Adenocarcinomas account for 10% of female urethral carcinomas, of which 40% are the clear cell variant. Determining the presence or absence of certain mutations through genetic testing may predict whether a patient with cancer may benefit from a particular chemotherapy regimen. Case summary A 40-year-old woman presented with a 3-year history of slow urinary flow and a 3-mo history of urinary urgency and frequency as well as gross hematuria. An abdominal and pelvic computed tomography scan demonstrated enlarged lymph nodes in the abdomen and pelvis. A biopsy of a left inguinal lymph node microscopically confirmed a metastatic adenocarcinoma of the urethra. Specialized genetic testing determined personalized chemotherapy. She was treated successfully with a non-platinum-based chemotherapy consisting of paclitaxel and bevacizumab. Following 3 cycles of paclitaxel and bevacizumab, she attained significant clinical improvement, and response by FDG-Positron emission tomography (PET) imaging showed a definite improvement in size and metabolic activity. She achieved complete response after 6 cycles of therapy by PET scan. The patient concluded 11 cycles of paclitaxel and bevacizumab, and a subsequent PET scan confirmed progression of metastatic disease. The patient was then treated with two cycles of doxorubicin after which a PET scan revealed a mixed response to the treatment. Conclusion We report the first case of a patient with metastatic clear cell adenocarcinoma of the urethra who underwent personalized chemotherapy after testing for cancer gene alterations. Our unique case represents the safe and effective use of non-platinum-based chemotherapy in clear cell adenocarcinoma of the urethra.

Background Retroperitoneal lymph node dissection (RPLND) plays a diagnostic, therapeutic, and prognostic role in myriad urologic malignancies, including testicular carcinoma, renal cell carcinoma (RCC), and upper urinary tract urothelial carcinoma. RCC represents 2% of all cancers with approximately 25% of patients presenting with advanced disease. Clear cell RCC (CCRCC) is the most common RCC, accounting for 75%-80% of all RCC. Case summary A 71-year-old man presented with a history of benign prostatic hypertrophy. He was asymptomatic without any hematuria, pain, or other urinary symptoms. A computed tomography (CT) scan of the abdomen and pelvis showed a 1.8 cm left retroperitoneal lymph node. There was no evidence of renal pathology. A core biopsy was performed of the left para-aortic lymph node. Although the primary tumor site was unknown, the morphological and immunohistochemical features were most consistent with CCRCC. A RPLND was performed which revealed a single mass 5.5 cm in greatest dimension with extensive necrosis. The retroperitoneal lymph node was most compatible with CCRCC. A nephrectomy was not conducted as a renal mass had not been detected on any prior imaging studies. The patient did not receive any type of adjuvant therapy. The patient underwent surveillance with serial CT scans with contrast of the chest, abdomen, and pelvis for the next 5 years, all of which demonstrated no recurrent or metastatic disease and no evidence of retroperitoneal adenopathy. Conclusion Our unique case emphasizes the therapeutic role of metastasectomy in metastatic CCRCC even in the absence of primary tumor in the kidneys.

INTRODUCTION AND OBJECTIVE:Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is a hereditary condition characterized by an increased risk for a clinically aggressive papillary renal cell c...

PURPOSE Patients with metastatic urothelial carcinoma (mUC) who progress on platinum-based combination chemotherapy (PLT) and checkpoint inhibitors (CPIs) have limited options that offer objective response rates (ORRs) of approximately 10% with a median overall survival (OS) of 7-8 months. Sacituzumab govitecan (SG) is a TROP-2–directed antibody-drug conjugate with an SN-38 payload that has shown preliminary activity in mUC. METHODS TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973 ) is a multicohort, open-label, phase II, registrational study. Cohort 1 includes patients with locally advanced or unresectable or mUC who had progressed after prior PLT and CPI. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary outcome was centrally reviewed ORR; secondary outcomes were progression-free survival, OS, duration of response, and safety. RESULTS Cohort 1 included 113 patients (78% men; median age, 66 years; 66.4% visceral metastases; median of three [range, 1-8] prior therapies). At a median follow-up of 9.1 months, the ORR was 27% (31 of 113; 95% CI, 19.5 to 36.6); 77% had decrease in measurable disease. Median duration of response was 7.2 months (95% CI, 4.7 to 8.6 months), with median progression-free survival and OS of 5.4 months (95% CI, 3.5 to 7.2 months) and 10.9 months (95% CI, 9.0 to 13.8 months), respectively. Key grade ≥ 3 treatment-related adverse events included neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%), with 6% discontinuing treatment because of treatment-related adverse events. CONCLUSION SG is an active drug with a manageable safety profile with most common toxicities of neutropenia and diarrhea. SG has notable efficacy compared with historical controls in pretreated mUC that has progressed on both prior PLT regimens and CPI. The results from this study supported accelerated approval of SG in this population.

Summary Background Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma. Method In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2–4a or ypN+ tumours following neoadjuvant chemotherapy or pT3–4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients. Findings Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2–29·8). Median disease-free survival was 19·4 months (95% CI 15·9–24·8) with atezolizumab and 16·6 months (11·2–24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74–1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group. Interpretation To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time. Funding F Hoffmann-La Roche/Genentech.

Although urothelial carcinoma (UC) is considered a chemotherapy-sensitive tumor, progression-free survival and overall survival (OS) are typically short following standard first-line (1L) platinum-containing chemotherapy in patients with locally advanced or metastatic disease. Immune checkpoint inhibitors (ICIs) have antitumor activity in UC and favorable safety profiles compared with chemotherapy; however, trials of 1L ICI monotherapy or chemotherapy + ICI combinations have not yet shown improved OS vs chemotherapy alone. In addition to direct cytotoxicity, chemotherapy has potential immunogenic effects, providing a rationale for assessing ICIs as switch-maintenance therapy. In the JAVELIN Bladder 100 phase 3 trial, avelumab administered as 1L maintenance with best supportive care (BSC) significantly prolonged OS vs BSC alone in patients with locally advanced or metastatic UC that had not progressed with 1L platinum-containing chemotherapy (median OS, 21.4 vs 14.3 months; hazard ratio, 0.69 [95% CI, 0.56–0.86]; P = 0.001). Efficacy benefits were seen across various subgroups, including recipients of 1L cisplatin- or carboplatin-based chemotherapy, patients with PD-L1+ or PD-L1− tumors, and patients with diverse characteristics. Results from JAVELIN Bladder 100 led to the approval of avelumab as 1L maintenance therapy for patients with locally advanced or metastatic UC that has not progressed with platinum-containing chemotherapy. Avelumab 1L maintenance is also included as a standard of care in treatment guidelines for advanced UC with level 1 evidence. This review summarizes the data that supported these developments and discusses practical considerations for administering avelumab maintenance in clinical practice, including patient selection and treatment management.

Purpose To assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of niraparib with apalutamide or abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods BEDIVERE was a multicenter, open-label, phase 1b study of niraparib 200 or 300 mg/day with apalutamide 240 mg or AAP (abiraterone acetate 1000 mg; prednisone 10 mg). Patients with mCRPC were previously treated with ≥ 2 lines of systemic therapy, including ≥ 1 androgen receptor-axis-targeted therapy for prostate cancer. Results Thirty-three patients were enrolled (niraparib-apalutamide, 6; niraparib-AAP, 27). No dose-limiting toxicities (DLTs) were reported when combinations included niraparib 200 mg; five patients receiving niraparib 300 mg experienced DLTs [niraparib-apalutamide, 2/3 patients (66.7%); niraparib-AAP, 3/8 patients (37.5%)]. Although data are limited, niraparib exposures were lower when given with apalutamide compared with historical niraparib monotherapy exposures in patients with solid tumors. Because of the higher incidence of DLTs, the niraparib–apalutamide combination and niraparib 300 mg combination with AAP were not further evaluated. Niraparib 200 mg was selected as the RP2D with AAP. Of 19 patients receiving niraparib 200 mg with AAP, 12 (63.2%) had grade 3/4 treatment-emergent adverse events, the most common being thrombocytopenia (26.3%) and hypertension (21.1%). Five patients (26.3%) had adverse events leading to treatment discontinuation. Conclusions These results support the choice of niraparib 200 mg as the RP2D with AAP. The niraparib–AAP combination was tolerable in patients with mCRPC, with no new safety signals. An ongoing phase 3 study is further assessing this combination in patients with mCRPC. Trial registration no. NCT02924766 (ClinicalTrials.gov).

BACKGROUND Testicular germ cell tumor (TGCT) is the most curable solid tumor and most common cancer among men 18-39 years. While cisplatin-based chemotherapy has significantly lengthened the survival of patients with TGCT, it is associated with a high rate of thromboembolic events (TEE). AIM To summarize our single-center experience highlighting patients who were diagnosed with TGCT and received platinum-based chemotherapy, with special attention to those patients who suffered a TEE. METHODS A retrospective analysis of the medical records and imaging studies of 68 consecutive individuals who were diagnosed with TGCT and received platinum-based chemotherapy at our Institution in a metropolitan community between January 1, 2014 and December 31, 2019. RESULTS A total of 19 (28%) patients experienced a TEE following orchiectomy which occurred during chemotherapy in 13 (68%) of these patients. Patients with a higher pathologic stage (stage III) were significantly (P = 0.023) more likely to experience a TEE compared to patients who had a lower stage. Additionally, patients who were treated with 3 cycles of bleomycine, etoposide, and cisplatin and 1 cycle of etoposide and cisplatin or 4 cycles of etoposide and cisplatin were significantly 5 (P = 0.02) times more likely to experience a TEE compared to patients who were treated with only 3 cycles of bleomycine, etoposide, and cisplatin. CONCLUSION Due to numerous factors that predispose to a TEE such as large retroperitoneal disease, higher clinical stage, greater number of chemotherapy cycle, central venous catheter, cigarette smoking, and possible cannabis use, high-risk ambulatory patients with TGCT treated with cisplatin-based chemotherapy may benefit from prophylactic anticoagulation. Randomized studies to evaluate the safety and efficacy of prophylactic anticoagulants are warranted in this young patient population generally devoid of medical co-morbidities.

Background: IMvigor130 evaluated atezo + plt/gem (Arm A) vs placebo + plt/gem (Arm C) as 1L mUC treatment, allowing pts with at least SD to continue atezo or placebo “maintenance” after 4-6 cycles of plt/gem. The primary analysis showed statistically significant PFS benefit for Arm A vs C (Galsky Lancet 2020). The 1st interim OS data for Arm A vs C were encouraging but immature. This exploratory analysis used 2nd interim OS data (ITT median follow-up, 13.3 mo) to examine OS outcomes by response during atezo or placebo + chemo “induction” in Arm A vs C. Methods: Pts were randomized 1:1:1 to Arm A, B (atezo monotherapy) or C. In Arms A and C, chemo was gem + investigator's choice of cis or carbo. Co-primary EPs of PFS and OS in Arm A vs C (ITT) and OS in Arm B vs C (ITT and IC2/3) were tested hierarchically. This post hoc analysis evaluated post-induction (post-wk 18) OS in pts who completed 4-6 (but not >6) cycles of chemo without PD during induction (through wk 18), followed by ≥1 dose of atezo or placebo maintenance. Post-PD OS was evaluated in pts with PD during induction. HRs were adjusted to account for potential imbalances in known prognostic factors between arms. Results: Efficacy data are in the Table. Post-induction OS HR (95% CI) for pts with no PD was 0.86 (0.64, 1.16) (cis: 0.60 [0.35, 1.03], carbo: 0.97 [0.67, 1.41]). Post-progression OS HR for pts with PD was 0.74 (0.53, 1.03) (cis: 0.52 [0.28, 0.96], carbo: 0.78 [0.51, 1.18]). Conclusions: In this exploratory analysis from IMvigor130, OS benefit with atezo + plt/gem vs placebo + plt/gem in both pts with and without PD during induction was consistent with ITT results from the 1st interim analysis. Preliminary data suggest that cis-treated pts may derive greater OS benefit from adding atezo to chemo than carbo-treated pts, which warrants further investigation. OS follow-up is ongoing. IMvigor130 efficacy (second interim OS analysis)No PD during inductiona (post-induction OS)bPD during induction (post-progression OS)Arm A (n=166)Arm C (n=152)Arm A (n=91)Arm C (n=93)OS events, n (%)ITT97 (58.4)92 (60.5)82 (90.1)84 (90.3)Cisplatinc27/57 (47.4)35/59 (59.3)24/29 (82.8)30/33 (90.9)Carboplatinc70/109 (64.2)57/93 (61.3)58/62 (93.5)54/60 (90.0)Median OS (95% CI), moITT20.5 (17.6, 25.9)18.8 (14.4, 21.9)4.3 (3.5, 5.8)3.3 (2.5, 4.4)Cisplatin28.2 (19.8, NE)19.9 (11.0, 26.5)6.6 (4.8, 10.1)2.5 (1.6, 5.2)Carboplatin18.5 (12.9, 21.6)18.8 (12.9, 22.8)3.8 (3.2, 5.6)3.4 (2.6, 4.5)OS HR (95% CI)dITT0.86 (0.64, 1.16)0.74 (0.53, 1.03)Cisplatin0.60 (0.35, 1.03)0.52 (0.28, 0.96)Carboplatin0.97 (0.67, 1.41)0.78 (0.51, 1.18)Data cutoff: June 14, 2020. 1L, first-line; carbo, carboplatin; chemo, chemotherapy; cis, cisplatin; CR, complete response; EP, endpoint; HR; hazard ratio; ITT, intention to treat; mets, metastases; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. a Pts who achieved at least SD (CR, PR, or SD without PD) during induction. b Post-week 18 OS. c Denominators refer to the number of pts in each chemotherapy subgroup/treatment arm. d Multivariable Cox proportional hazards model stratified by enrollment stage (1/2); adjusted for age, ECOG PS (0, 1, 2), cisplatin ineligibility (Y/N), liver mets (Y/N), lymph node mets only (Y/N), ≥3 metastatic sites (Y/N), renal impairment (Y/N), alkaline phosphatase ≥upper limit of normal (Y/N), glomerular filtration rate ( Citation Format: Enrique Grande, Aristotelis Bamias, Matthew D. Galsky, Eiji Kikuchi, Ian D. Davis, José Ángel Arranz, Arash Rezazadeh Kalebasty, Xavier Garcia del Muro, Se Hoon Park, Ugo De Giorgi, Boris Alekseev, Marina Mencinger, Kouji Izumi, Javier Puente, Jian-Ri Li, Xiaodong Shen, Beiying Ding, Qian Zhu, Jeremy Linsenmeier, Maria De Santis. Overall survival (OS) by response during “induction” from the global, randomized Phase III IMvigor130 study of atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with previously untreated metastatic urothelial carcinoma (mUC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT187.

Summary Background Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma. Methods In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov , NCT02807636 . Findings Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1–17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5–8·3) in group A and 6·3 months (6·2–7·0) in group C (stratified hazard ratio [HR] 0·82, 95% CI 0·70–0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9–18·9) in group A and 13·4 months (12·0–15·2) in group C (0·83, 0·69–1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1–17·8) for group B and 13·1 months (11·7–15·1) for group C (1·02, 0·83–1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo. Interpretation Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma. Funding F Hoffmann-La Roche and Genentech.

309 Background: The long-term efficacy and tolerability of nivolumab (NIVO) 3 mg/kg + ipilimumab (IPI) 1 mg/kg Q3W × 4 doses followed by NIVO 3 mg/kg Q2W for previously untreated advanced RCC (aRCC) demonstrated in the registrational CheckMate 214 clinical trial was based on patients (pts) with a predominantly clear cell component. CheckMate 920 (NCT02982954) is a US community-based, multi-arm, phase IIIb/IV clinical trial of NIVO+IPI treatment in pts with previously untreated aRCC and clinical features mostly excluded from phase III trials. Here, we present the safety and efficacy results for the cohort of pts with nccRCC from CheckMate 920, a patient population with a poor prognosis and without a definitive effective treatment. Methods: Pts with previously untreated advanced/metastatic nccRCC, Karnofsky performance status ≥ 70%, and any International Metastatic Renal Cell Database Consortium risk received NIVO 3 mg/kg + IPI 1 mg/kg (NIVO3+IPI1) Q3W × 4 doses followed by NIVO 480 mg Q4W for ≤ 2 years or until disease progression/unacceptable toxicity. The primary endpoint was incidence of any-causality grade ≥ 3 immune-mediated adverse events (imAEs) within 100 days of last dose of study drug. Key secondary endpoints: progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 (both per investigator), duration of response (DOR), and time to response (TTR). Exploratory endpoints included overall survival (OS). Results: Of 52 treated pts with nccRCC, 69.2% were men; median age was 64 years (range, 23–86), and 28.8% had sarcomatoid features. Histological subtypes were papillary (34.6%), chromophobe (13.5%), translocation associated (3.8%), collecting duct (3.8%), renal medullary (1.9%), or unclassified (42.3%). With 24.1 months minimum follow-up, median duration of therapy (range) was 3.5 months (0.0–25.8) for NIVO and 2.1 months (0.0–3.9) for IPI. Median (range) number of doses received was 4.5 (1–28) for NIVO and 4.0 (1–4) for IPI. No grade 5 imAEs occurred. Grade 3–4 imAEs (n = 52) by category were diarrhea/colitis (7.7%), rash (5.8%), nephritis and renal dysfunction (3.8%), hepatitis (1.9%), adrenal insufficiency (1.9%), and hypophysitis (1.9%). ORR (n = 46) was 19.6% (95% CI, 9.4–33.9). Two pts achieved complete response (papillary, n = 1; unclassified pathology, n = 1), 7 achieved partial response (papillary, n = 4; unclassified pathology, n = 3), and 17 pts had stable disease. Median TTR was 2.8 months (range, 2.1–4.8). Median DOR was not reached (range, 0.03+–27.8+); 8 of 9 responders remain without reported progression. Median PFS (n = 52) was 3.7 months (95% CI, 2.7–4.6). Median OS (n = 52) was 21.2 months (95% CI, 16.6–not reached). Conclusions: In pts with previously untreated nccRCC, a population with high unmet medical need, treatment with NIVO3+IPI1 Q3W followed by NIVO 480 mg Q4W showed no new safety signals, and encouraging antitumor activity. Clinical trial information: NCT02982954 .

e17578 Background: Both abiraterone and enzalutamide have been approved for the treatment of mCRPC. GT0918 (proxalutamide) is a novel second-generation androgen receptor (AR) antagonist binding directly to the androgen receptor, impairing nuclear translocation and decreasing AR protein expression. This phase II portion of the Ph I/II study is being conducted to further evaluate safety and tolerability of GT0918 at 400 mg or 500 mg daily dosing. Methods: All eligible mCRPC pts with progressive disease based on rising prostate-specific antigen (PSA) or/and imaging while on either abiraterone or enzalutamide, but not both. One line of prior chemotherapy was allowed. Pts (n = 60) will be randomized to GT0918 either 400 mg or 500 mg po once daily for 6 months. The primary endpoint is safety and tolerability. Secondary endpoints are PSA reduction at 12 weeks, % radiographic progression at 6-month, time to imaging progression, and exploratory biomarker CTC & cf-DNA/RNA. PSA is assessed every 4 wks and tumor imaging is done every 12 wks. Results: 56 pts were screened June 2019 to January 15, 2020 and 40 pts were randomized to receive GT0918 either 400 mg or 500 mg po daily. 22 pts (55%) had enzalutamide as prior therapy and 18 pts (45%) had abiraterone as prior therapy. 17 pts (43%) had one or more lines of chemotherapy. The median age was 72 years (range 53-89) and median baseline PSA was 162 ng/mL (0.3-4195). 10 pts had 1 cycle or less of study drug due to rapid PSA progression, AEs and/or withdrawal of consent. The most common treatment-related AEs were fatigue (48%), loss of appetite/anorexia (25%), nausea (20%), lower leg extremity edema (18%), constipation (15%), weight loss (13%), vomiting (10%), and headache (8%). 8 pts (6 in 500 mg vs. 2 in 400 mg) required dose reduction due to AE. No seizures have been observed. As Jan 30, 2020, 3 pts (8%) and 8 pts (20%) had PSA reduction at 12 weeks and 4 weeks, respectively, but no 50% PSA reduction was observed. 2 pts (5%) received study drug treatment over 24 weeks and 10 pts (25%) received study drug over 16 weeks based on stable disease (SD) on imaging. Conclusions: GT0918 administrated orally once a day is well tolerated and first 40-pts taking GT0918 show some anti-tumor activities. Dose of 400 mg po daily is recommended for GT 0918 for further clinical trials. Clinical trial information: NCT03899467 .

TPS591 Background: Although CIT has efficacy against multiple cancers, only subsets of patients (pts) have durable responses with monotherapy. CIT combination treatment (tx) targets multiple immune-evasion mechanisms and may thus be more likely to improve outcomes. However, a large number of potential combinations need to be tested to identify effective combinations. The MORPHEUS platform comprises multiple global, open-label, randomized Phase Ib/II trials to identify early efficacy signals and safety of tx combinations in pts with different cancers. MORPHEUS-mUC is a randomized study of 6 CIT combinations compared with a single CIT control in pts with locally advanced UC/mUC who progressed during or after a platinum-containing regimen. The PD-L1 inhibitor atezolizumab will be combined with agents targeting different mechanisms (via nectin-4, PARP, CD47, CD38, DPP-4 and IL-6R) to simultaneously enhance immune cell priming and activation, tumor infiltration and/or recognition of tumor cells. To accelerate the clinical development of novel combinations, MORPHEUS has the flexibility, via amendment, to allow for the modification of eligibility criteria or the opening of new tx arms to replace arms that demonstrate no signs of clinical activity/unacceptable toxicity. Methods: MORPHEUS-mUC (NCT03869190) has 2 stages. In Stage 1, approximately 130-305 pts with histologically documented, locally advanced inoperable UC/mUC will be randomized to atezolizumab monotherapy (control) or experimental arms: atezolizumab + either enfortumab vedotin, niraparib, magrolimab (Hu5F9-G4), isatuximab, linagliptin or tocilizumab. Safety will be monitored for potential overlapping toxicities. Stage 2 arms will be atezolizumab + either enfortumab vedotin or linagliptin arms, unless these combinations show no activity in Stage 1. Eligible pts who experience unacceptable toxicity or loss of clinical benefit in Stage 1 may enroll in Stage 2 within 3 months. The primary study endpoint is investigator-assessed ORR per RECIST 1.1; secondary endpoints include PFS, OS, DOR, DCR and safety. Biomarkers will also be explored. Clinical trial information: NCT03869190.

Background The antitumor activity of programmed death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibition alone is limited in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Combining immunotherapy with standard-of-care chemotherapy could improve outcomes in mCRPC. We report interim analysis results for the nivolumab + docetaxel (NIVO+DOCE) treatment arm from CheckMate 9KD. Methods CheckMate 9KD is a phase II study of NIVO in combination with DOCE, rucaparib, or enzalutamide. Eligible pts had confirmed metastatic adenocarcinoma of the prostate, ongoing androgen deprivation therapy, and evaluable tumor biopsy. Pts assigned to NIVO+DOCE (chemotherapy-naive and received ≤2 prior second-generation hormonal therapies) received NIVO 360mg every 3 weeks + DOCE 75mg/m2 every 3 weeks + prednisone 5mg twice daily for ≤10 cycles followed by NIVO 480mg every 4 weeks alone until disease progression or unacceptable toxicity (up to 2 years). Coprimary endpoints were objective response rate (ORR) and prostate-specific antigen response rate (PSA-RR; defined as≥50% PSA reduction from baseline). Secondary endpoints included radiographic progression-free survival (rPFS), and safety/tolerability in all treated pts. Association of biomarkers with efficacy was an exploratory endpoint. Results This interim analysis included 41 pts in the NIVO+DOCE arm with a minimum follow-up of 28 weeks, of whom 19 (46.3%) had measurable disease. At the time of the analysis, 24 (58.5%) had discontinued study treatment. ORR in pts with measurable disease was 36.8% (95% confidence interval [CI], 16.3–61.6) with 1 complete response and 6 partial responses. Confirmed PSA-RR was 46.3% (95% CI, 30.7–62.6). Median rPFS was 8.2 months (95% CI, 6.6–not estimable). The 6-month rPFS rate was 71.5%. Any-grade and grade 3/4 treatment-related adverse events occurred in 92.7% and 48.8% of pts, respectively. Associations of biomarkers are also evaluated. Conclusions The combination of NIVO+DOCE showed encouraging clinical activity in pts with mCRPC, with a safety profile consistent with those of the individual agents. A phase III trial is warranted to further evaluate NIVO+DOCE in mCRPC. Clinical trial identification NCT03338790. Editorial acknowledgement Professional medical writing assistance was provided by Nicolette Belletier, PhD, of Parexel, and funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb and Ono Pharmaceutical Company Limited. Disclosure K. Fizazi: Advisory / Consultancy: Janssen; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: Orion. A. Rezazadeh Kalebasty: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Exelexis; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AZ; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Macrogenics; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Beyond Spring; Research grant / Funding (institution): Bioclin/Rainier Therapeutics; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Bavarian; Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Seattle Genetics; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Shareholder / Stockholder / Stock options: ECOM; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Speaker Bureau / Expert testimony: Amgen; Travel / Accommodation / Expenses: Prometheus Labs. J.C. Vazquez Limon: Non-remunerated activity/ies, Personal Fees and non-financial support: AstraZeneca; Non-remunerated activity/ies, Non-financial support: Merck; Non-remunerated activity/ies, Personal fees: Roche; Non-remunerated activity/ies, Personal fees: Bristol-Myers Squibb. A.J. Armstrong: Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Pfizer/Astellas; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Dendreon; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Byer; Research grant / Funding (institution): Constellation; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Clovis. B. Sharkey: Full / Part-time employment: Bristol-Myers Squibb. A. Saci: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. J. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. X. Wang: Full / Part-time employment: Bristol-Myers Squibb. M. Ciprotti: Full / Part-time employment: Bristol-Myers Squibb. P. Sathyanarayana: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. F. Saad: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer. D.P. Petrylak: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Bellicum; Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Endocyte ; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ferring; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Innocrin; Advisory / Consultancy, Research grant / Funding (institution): Johnson and Johnson; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Millineum; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Progenics; Research grant / Funding (institution): Roche Labatories; Advisory / Consultancy, Research grant / Funding (institution): Sanofi Aventis; Research grant / Funding (institution): Sotio; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Tyme Pharmaceuticals. R.K. Pachynski: Advisory / Consultancy, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony: Dendreon; Advisory / Consultancy: EMD Serono/Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genomic Health; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy: Jounce Therapeutics. C. Drake: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Compugen; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): Janssen Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Astellas Medivation; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tizona Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: F-Star; Advisory / Consultancy, Shareholder / Stockholder / Stock options: KLEO; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Harpoon; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Shattuck Labs; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Werewolf; Advisory / Consultancy: Genocea; Advisory / Consultancy: Sanofi Aventis; Advisory / Consultancy, Licensing / Royalties: Amplimmune; Advisory / Consultancy, Licensing / Royalties: BMS; Advisory / Consultancy: EMD. All other authors have declared no conflicts of interest.

Background Patients (pts) with mUC who have failed platinum-based chemotherapy have a poor prognosis. Reported response rates to immune checkpoint inhibitors (ICI) are approximately 20%. Pts that harbor FGFR3 mutations or fusions (M/F) or have high FGFR3 expression, may have a lower sensitivity to ICI. V (B-701) is a fully human monoclonal antibody against FGFR3 that blocks activation of both the wildtype and genetically activated receptor. FIERCE-22 is a Phase 1b/2 study designed to evaluate V in combination with P (VP). Methods The phase 2 (P2) study enrolled mUC pts who had failed to ≥ 1 prior line of chemotherapy or had recurred within 12 months of (neo)adjuvant chemotherapy. Pts had measurable disease and ECOG Results In the P2, 28 pts have received treatment (wild-type (WT):20, M/F: 8). Patients were unselected for PD-1 status, predominately male (55%) white (95%), all had received at least 1 line of prior chemo and 60% had Bellmunt score of > 1. The safety profile was consistent with previously reported data for P. TEAE occurring in > 20% of patients were anemia, fatigue, pyrexia, and diarrhea. V-related TEAEs reported in > 2 pts were diarrhea, fatigue and pyrexia. The combination was active across M/F and WT tumors as previously reported. At median follow-up time of 7.5 months, the ORR in the tumor response evaluable population is 29.6% and the median PFS is 4.7 months. Nine pts (32%) are continuing study treatment plus 9 pts are in long-term survival follow up. Conclusions VP combination therapy is well tolerated with encouraging ORR and prolonged PFS compared to historical data from P alone. We will present updated safety and efficacy data including OS at 12 months. Clinical trial identification NCT03123055. Legal entity responsible for the study Rainier Therapeutics, Inc. Funding Rainier Therapeutics, Inc. Disclosure A.O. Siefker-Radtke: Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: Nektar Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Seattle Genetics; Advisory / Consultancy: Bavarian Nordic. I. Lugowska: Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Research grant / Funding (self): Merck; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self): Amgen; Honoraria (self): Janssen; Honoraria (self), Research grant / Funding (self): Novartis. A. Rezazadeh Kalebasty: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Exelexis; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Macrogenics; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Beyond Spring; Research grant / Funding (institution): Rainier Therapeutics; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Seattle Genetics; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Shareholder / Stockholder / Stock options: ECOM; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Speaker Bureau / Expert testimony: Amgen; Travel / Accommodation / Expenses: Prometheus labs. G. Curigliano: Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Seagen. F.D. Vogl: Full / Part-time employment: Rainier Therapeutics. G. Currie: Full / Part-time employment, Officer / Board of Directors: Rainier Therapeutics. S. Abella: Full / Part-time employment, Officer / Board of Directors: Rainier Therapeutics. All other authors have declared no conflicts of interest.

4517 Background: Previous clinical trials of patients (pts) with aRCC, including CheckMate 214, have mostly excluded pts with brain metastases. However, antitumor activity in pts with brain metastases has been observed in pts with melanoma treated with NIVO 1 mg/kg + IPI 3mg/kg and pts with non-small cell lung cancer treated with NIVO 240 mg + IPI 1mg/kg. CheckMate 920 is an ongoing, phase 3b/4 clinical trial of NIVO + IPI treatment in pts with aRCC with a high unmet medical need. Here, we present the safety and efficacy interim results for the cohort of pts with brain metastases. Methods: Pts with previously untreated aRCC of any histology, with asymptomatic brain metastases (not on corticosteroids or receiving radiation), and Karnofsky performance status ≥70% were assigned to treatment with NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks for 4 doses, followed by NIVO 480 mg every 4 weeks. Pts were treated until disease progression, unacceptable toxicity, or for a maximum of 2 years. The primary endpoint was the incidence of high-grade immune-mediated adverse events (IMAEs). Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 per investigator. Exploratory endpoints included additional safety analyses and overall survival (OS). Results: Overall, 28 patients were enrolled in the brain metastases cohort. With a minimum follow-up of 6.47 months, grade 3-4 IMAEs within 100 days of last dose were reported in 6 cases. The grade 3-4 IMAEs observed in ≥ 1 patient were diarrhea, colitis, diabetic ketoacidosis, immune-mediated hepatitis, hypophysitis, and rash of any type (n = 1 each). No treatment-related grade 5 IMAEs were reported. ORR by RECIST v1.1 per investigator in all treated subjects was 28.6% (95% CI 13.2–48.7). Median PFS in all treated subjects was 9.0 months (95% CI 2.9–not estimable [NE]). Median OS has not been reached (95% CI 13.1–NE). Conclusions: In pts with aRCC and brain metastases who are often excluded from clinical trials, NIVO + IPI treatment showed a safety profile consistent with previous reports of this dosing regimen, with encouraging antitumor activity. Clinical trial information: NCT02982954.

Robert Dreicer*, Charlottesville, VA; Michiel S. van der Heijden, Amsterdam, Netherlands; Petros Grivas, Cleveland, OH; Jean Hoffman-Censits, Philadelphia, PA; Yohann Loriot, Villejuif, France; Margitta Retz, Munich, Germany; Nicholas J Vogelzang, Las Vegas, NV; Jose Luis Perez-Gracia, Pamplona, Spain; Arash Rezazadeh Kalebasty, Louisville, KY; Sergio Bracarda, Arezzo, Italy; Evan Y Yu, Seattle, WA; Christopher Hoimes, Cleveland, OH; Joaquim Bellmunt, Boston, MA; David I Quinn, Los Angeles, CA; Daniel P. Petrylak, New Haven, CT; Syed A Hussain, Liverpool, United Kingdom; Na Cui, Sanjeev Mariathasan, Fatema Legrand, South San Francisco, CA; Jonathan E. Rosenberg, New York, NY

141 Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mCRPC pts, Cabo was associated with improvements in pain, bone scans, measurable disease, and circulating tumor cells. COMET-2 compared the effects of Cabo versus MP on pain palliation in men with progressive mCRPC. Methods: In this double-blind, controlled phase 3 study (NCT01522443), pts with moderate to severe pain and disease progression following D, and A and/or E were randomized 1:1 to receive Cabo (60 mg qd) or MP (12 mg/m2 q3wk and 5 mg bid, resp). All pts were required to have a 7-day average of 4+ pain per Brief Pain Inventory (BPI) item 3 while on an optimized narcotics regimen at baseline. Randomization was stratified by prior cabazitaxel and ECOG performance status. The primary endpoint was pain response (≥30% reduction in BPI item 3) at week 6, confirmed at week 12, without increase in narcotics. The original sample size (N = 246) was selected to achieve at least 90% power to detect an increase in pain response with Cabo (25%) vs. MP (8%) using a two-sided α = 0.05 chi-squared test. The secondary efficacy endpoints were bone scan response (BSR) and overall survival (OS). Results: 119 pts were randomized between March 2012 and July 2014. Randomization was concluded prior to reaching the planned sample size because the companion study COMET-1 did not show a significant OS benefit compared to P in a similar population. Pain response rates were 15% for Cabo vs 17% for MP (P = 0.773). BSR rates were 31% for Cabo vs 5.2% for MP. Median OS was 9 months for Cabo vs 7.9 months for MP. Most frequent G3/4 AEs in the Cabo arm were anemia (22% vs 26% MP), hypertension (22% vs 0% MP), fatigue (18% vs 8.8% MP), and AST increased (10% vs 1.8% MP), with fewer pts discontinuing study treatment for AEs in the Cabo arm (16% vs 26% MP). Conclusions: The primary endpoint of improving pain response was not achieved in this heavily pretreated population. The key secondary endpoints of BSR and OS showed trends favoring the Cabo arm, and no new safety signals were observed at the dose of 60 mg. Clinical trial information: NCT01522443.