Background.
Prostate cancer (PC) is the most commonly diagnosed noncutaneous malignancy in American men. PC, which exhibits a slow growth rate and multiple potential target epitopes, is an ideal ...candidate for immunotherapy. GVAX for prostate cancer is a cellular immunotherapy, composed of PC‐3 cells (CG1940) and LNCaP cells (CG8711). Each of the components is a prostate adenocarcinoma cell line that has been genetically modified to secrete granulocyte‐macrophage colony‐stimulating factor. Hypothesizing that GVAX for prostate cancer could be effective in a neoadjuvant setting in patients with locally advanced disease, we initiated a phase II trial of neoadjuvant docetaxel and GVAX. For the trial, the clinical effects of GVAX were assessed in patients undergoing radical prostatectomy (RP).
Methods.
Patients received docetaxel administered at a dose of 75 mg/m2 every 3 weeks for 4 cycles. GVAX was administered 2–3 days after chemotherapy preoperatively for four courses of immunotherapy. The first dose of GVAX was a prime immunotherapy of 5×108 cells. The subsequent boost immunotherapies consisted of 3×108 cells. After RP, patients received an additional six courses of immunotherapy. Pathologic complete response, toxicity, and clinical response were assessed. The primary endpoint of the trial was a pathologic state of pT0, which is defined as no evidence of cancer in the prostate.
Results.
Six patients completed neoadjuvant docetaxel and GVAX therapy. No serious drug‐related adverse events were observed. Median change in prostate‐specific antigen (PSA) following neoadjuvant therapy was 1.47 ng/ml. One patient did not undergo RP due to the discovery of positive lymph nodes during exploration. Of the five patients completing RP, four had a downstaging of their Gleason score. Undetectable PSA was achieved in three patients at 2 months after RP and in two patients at 3 years after RP.
Conclusions.
Neoadjuvant docetaxel/GVAX is safe and well tolerated in patients with high‐risk locally advanced PC. No evidence of increased intraoperative hemorrhage or increased length of hospital stay postoperatively was noted. These results justify further study of neoadjuvant immunotherapy.
摘要
背景. 前列腺癌（PC）是美国男性中最常诊断的非皮肤恶性肿瘤。PC进展缓慢，且具有多种潜在的靶位抗原，因此是免疫疗法的理想治疗对象。GVAX由PC‐3细胞（CG1940）和LNCaP细胞（CG8711）组成，是一种用于前列腺癌治疗的细胞免疫治疗法。两种细胞均为经基因修饰后可分泌粒细胞巨噬细胞集落刺激因子的前列腺腺癌细胞系。基于GVAX在局部晚期前列腺癌患者新辅助治疗中可能有效的假说，我们开展了一项关于多西他赛新辅助治疗联合GVAX治疗的II期研究；并在本研究中评估了GVAX在接受前列腺根治术（RP）患者中的临床作用。
方法. 给予患者多西他赛75mg/m2每3周一次治疗，共4周期。化疗后2 ∼3天给予GVAX作为术前免疫治疗，共4周期。首剂GVAX为5 ×108细胞的启动剂量免疫治疗，后续加强治疗的剂量为3×108细胞。RP术后患者将再接受6周期免疫治疗。评估患者的病理完全缓解、毒性事件和临床缓解率。研究的主要终点为pT0病理状态，定义为前列腺部位无癌症证据。
结果. 6例患者完成了多西他赛联合GVAX的新辅助治疗。研究未观察到严重药物相关不良事件。新辅助治疗后患者前列腺特异性抗原（PSA）水平的中位变化值为1.47ng/ml。1例患者因研究期间发现阳性淋巴结而未行RP。5例完成RP的患者中，4例Gleason评分降级。3例患者的PSA水平在RP后2月不可测，2例患者在RP后3年不可测。
结论.多西他赛联合GVAX新辅助治疗在局部晚期高危前列腺癌患者中具有良好的安全性和耐受性。未见术中出血或术后住院时间延长的证据。上述结果支持就新辅助免疫治疗开展进一步研究。
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4546
Background: Initial results of the phase 2 KEYNOTE-052 (NCT02335424) study led to approval of pembro for cisplatin-ineligible patients (pts) with advanced UC. Updated results ...representing follow-up of over 2 y since last pt enrolled are presented. Methods: Pts had confirmed advanced UC, were cisplatin-ineligible (ECOG PS 2, CrCl ≥30 to ˂60 mL/min, grade ≥2 neuropathy/hearing loss, NYHA Class III heart failure), and received no prior chemotherapy for metastatic disease. Pts received pembro 200 mg IV Q3W until progression, unacceptable toxicity, withdrawal, or 24 mo of therapy, whichever occurred first. Primary end point was confirmed ORR (RECIST v1.1, independent central review). Key secondary end points: duration of response (DOR), overall survival (OS), and safety. Data cutoff was September 26, 2018. Results: Among pts assessed (N = 370), median age was 74 y, 85% had visceral disease, and 30% were PD-L1 positive (combined positive score CPS ≥10). Median follow-up was 11.4 mo (range, 0.1-41.2) for all pts and 29.3 mo (range 7-41.2) for responders. Confirmed ORR was 29% (95% CI, 24-34): complete response, 9% (n = 33); partial response, 20% (n = 73). Median DOR was 30.1 mo (95% CI, 18.1-not reached NR); 67% and 52% of pts had DOR ≥12 and ≥24 mo, respectively. Median OS was 11.3 mo (range 9.7-13.1); 12- and 24-mo OS rates were 47% and 31%, respectively. In pts with CPS ˂10 (n = 251) and ≥10 (n = 110), respectively, confirmed ORR was 20% (95%CI, 16-26) and 47% (95% CI, 38-57). Median DOR for pts with CPS < 10 and ≥10 was 18.2 mo (95% CI, 9.7-NR) and NR (95% CI, 18.1-NR); DOR ≥24 mo was 45% and 57%, respectively. Median OS for pts with CPS < 10 and ≥10 was 9.7 mo (95% CI, 7.6-11.5) and 18.5 mo (95% CI, 12.2-28.5); 24-mo OS rates were 24% and 47% respectively. Treatment-related adverse events (AEs) occurred in 67% of pts. Most common were fatigue and pruritus (18% each); 21% were grade ≥3, including 1 death (myositis). Conclusions: With extended follow-up, pembro continued to elicit clinically meaningful, durable antitumor activity in cisplatin-ineligible pts with advanced UC and was more pronounced in those with PD-L1 expression CPS ≥10. Pembro safety profile was as expected. Clinical trial information: NCT02335424.
Abstract
Background: Preclinical data suggest that combination of endocrine therapy (ET) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and mammalian target of rapamycin inhibitor (mTORi) may ...overcome prior treatment resistance in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). The Phase Ib CLEE011X2106 study (NCT01857193) is investigating ribociclib (RIB; CDK4/6i) + everolimus (EVE; mTORi) + exemestane (EXE; ET) in patients with HR+, HER2- ABC resistant to letrozole or anastrozole. The objective of this analysis is to characterize baseline gene expression patterns in the CDK4/6i-naïve and -refractory groups, and assess the potential correlation with clinical activities.
Methods: Postmenopausal women with HR+, HER2- ABC resistant to letrozole or anastrozole, and who had received no prior CDK4/6i or whose disease had progressed on or within 1 month of CDK4/6i therapy, were enrolled in the CDK4/6i-naïve and -refractory dose expansion groups, respectively. More than 1 line of chemotherapy for ABC or prior treatment with EXE or an mTORi was not permitted. Patients received RIB (300 mg, 3-weeks on/1-week off) + EVE (2.5 mg, continuous) + EXE (25 mg, continuous) until disease progression or study discontinuation. Baseline tumor samples (collected after CDK4/6i therapy in the CDK4/6i-refractory group) were assessed for mRNA expression using the NanoString 230-gene nCounter® GX Human Cancer Reference panel.
Results: As of May 15, 2017, the 24-week clinical benefit rate was 56% (9/16) in the CDK4/6i-naïve group and 24% (4/17) in the -refractory group. Baseline tumor mRNA expression was evaluable in 14 patients: CDK4/6i naïve, n=8 (best response: 7 stable disease SD, 1 progressive disease PD); CDK4/6i refractory, n=6 (2 SD, 4 PD). Across all patients (both groups), those with SD tended to have higher ESR1 expression compared with those experiencing PD, with a trend for higher baseline ESR1 expression in the CDK4/6i-naïve group compared with the -refractory group. Also across all patients, higher overall baseline expression of cell cycle control genes and mitogen-activated protein kinase (MAPK) pathway genes appeared to trend with PD. Additionally, in the CDK4/6i-refractory group, there was a trend for higher CDK2 and/or CCNE1 expression in patients with PD compared with SD. A heat map of 24 genes indicated differences in gene expression patterns between the CDK4/6i-naïve and -refractory groups.
Conclusions: Gene expression patterns differ between CDK4/6i-naïve and -refractory tumors. Higher expression of cell cycle control genes (particularly CDK2 and CCNE1) and MAPK pathway genes appears to trend with resistance to the RIB + EVE + EXE combination after progression on prior CDK4/6i. Due to the small number of samples, further investigation is needed.
Citation Format: Aditya Bardia, Shanu Modi, Javier Cortes, Mario Campone, Luc Dirix, Brigette Ma, J Thaddeus Beck, Jorge Chaves, Amy Weise, Jacqueline Vuky, Gilberto Lopes, Miguel Gil-Gil, Xiaochun Liu, Wei He, Faye Su, Michelle Miller, Mariana Chavez-MacGregor. Baseline gene expression patterns of CDK4/6 inhibitor-naïve or -refractory HR+, HER2- advanced breast cancer in the phase Ib study of ribociclib plus everolimus plus exemestane abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT069.
Patients with treatment-naive advanced urothelial cancer (UC) ineligible for cisplatin-based chemotherapy are typically older and have comorbidities, representing a difficult-to-treat population.
To ...evaluate the safety and antitumor activity of first-line pembrolizumab in subgroups of cisplatin-ineligible older patients (aged ≥65 and ≥75 yr) with advanced UC in KEYNOTE-052 (NCT02335424), including those with poor performance status (Eastern Cooperative Oncology Group performance status score 2 ECOG PS2).
Patients were cisplatin ineligible, had treatment-naive, histologically/cytologically confirmed, locally advanced/metastatic UC with measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1 RECIST v1.1), and had ECOG PS0–2. Patient subgroups analyzed were aged ≥65yr (n = 302), ≥75 yr (n = 179), ≥65yr with ECOG PS2 (≥65yr+ECOG PS2; n = 119), and ≥75 yr+ECOG PS2 (n = 78).
All patients received pembrolizumab 200mg intravenously every 3 wk until confirmed progression, intolerable toxicity, patient withdrawal, or 24 mo of therapy.
The primary endpoint was objective response rate (ORR) as per RECIST v1.1. The key secondary endpoints were overall survival (OS), duration of response (DOR), and safety.
ORRs for the ≥65yr, ≥75 yr, ≥65yr+ECOG PS2, and ≥75 yr+ECOG PS2 subgroups were 29%, 27%, 29%, and 31%, respectively; rates of complete and partial responses were similar across subgroups (9%, 5%, 6%, and 6%, and 20%, 22%, 23%, and 24%, respectively). Median DOR and OS were also consistent across the ≥65yr and ≥65yr+ECOG PS2 subgroups and the ≥75 yr and ≥75 yr+ECOG PS2 subgroups. Study limitations included open-label design, lack of a comparator group, and nature of post hoc exploratory analysis.
The clinical benefit of pembrolizumab in advanced UC appeared to be consistent regardless of age and/or poor performance status.
This study looked at whether older age and poorer performance status affect how well patients with previously untreated advanced urothelial cancer ineligible for standard-of-care treatment respond to pembrolizumab. Outcomes with pembrolizumab were not affected by older age or poorer performance status, making it an effective option.
Pembrolizumab is effective and well tolerated in cisplatin-ineligible senior patients with advanced urothelial cancer, including those with poor performance status. Tumor response and outcomes were not impacted by poor performance status and/or older age.
Background Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. ...This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB). Patients and methods Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119 ). tTMB and bTMB were determined by the Foundation Medicine FoundationOne ® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab. Results In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals. Conclusions Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab. Trial registration number NCT03668119 .
A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum-resistant ovarian, ...peritoneal, or fallopian tube cancer (OC).
Patients were treated with bevacizumab 10 mg/kg on days 1 and 15 and topotecan 4 mg/m(2) on days 1, 8, and 15 of a 28-day cycle until progressive disease (PD) or excessive toxicity. The primary endpoint was progression-free survival (PFS); secondary objectives included overall survival (OS), objective response, and toxicity.
Patients (N = 40) received a median of 8 treatment cycles. Toxicity was generally mild or moderate, with neutropenia (18%), hypertension (20%), gastrointestinal toxicity (18%), pain (13%), metabolic toxicity (15%), bowel obstruction (10%), and cardiotoxicity (8%) being the most common grade 3 and 4 adverse events. No bowel perforations, febrile neutropenia, or treatment-related deaths occurred. Median PFS and OS were 7.8 (95% confidence interval CI, 3.0-9.4) and 16.6 months (95% CI, 12.8-22.9), with 22 (55%) patients progression-free for ≥6 months. Ten (25%) patients had partial response (PR), 14 (35%) had stable disease (SD), and 16 (40%) had PD. Patients treated with 2 prior regimens received greater benefit than patients treated with 1: PR/SD, 78.9% versus 42.9% (P = .03); median PFS, 10.9 versus 2.8 months (P = .08); median OS, 22.9 versus 12.8 months (P = .02).
A weekly topotecan and biweekly bevacizumab combination demonstrates acceptable toxicity and encouraging efficacy in patients with platinum-resistant OC; further study is warranted.
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4502
Background: Comorbidities and renal impairment preclude many with advanced UC from receiving chemotherapy. Initial results from the phase 2 KEYNOTE-052 (NCT02335424) trial ...suggested first-line pembro is active and safe in cisplatin-ineligible advanced UC. We present updated efficacy and safety data (all pts have ≥6 mo follow-up) and evaluate biomarkers correlated with outcomes. Methods: Eligibility criteria included cisplatin-ineligible (ECOG PS 2, CrCl ≥30- < 60 mL/min, grade ≥2 neuropathy/hearing loss, NYHA Class 3 heart failure), advanced UC, and no prior systemic chemotherapy. Pts received pembro 200 mg IV Q3W. Imaging was performed at wk 9, then Q6W for the first year, and Q12W thereafter. Primary end point was confirmed ORR (RECIST v1.1, independent review). Efficacy and safety were assessed in the 370 pts with ≥1 pembro dose. The associations of an 18-gene expression profile (GEP) and IHC PD-L1 combined positive score (CPS) with ORR were evaluated. Results: As of the Dec 19, 2016, data cutoff, ORR was 29% (95% CI, 24-34): 25 (7%) and 81 (22%) pts achieved complete and partial responses. Another 69 pts (19%) had stable disease as best response, for a clinical benefit rate of 47%. Median time to response was 2 mo (range, 1-5). At a median follow-up of 8 mo (range, 0.1-20) across all pts, median duration of response was not reached (range, 1+-18+ mo). 74% of responses were ongoing. Any-grade and grade ≥3 drug-related AEs occurred in 239 (65%) and 68 (18%) pts. Immune-mediated AEs occurred in 76 (21%) pts. Evidence supporting a positive association with response was seen in the first 100 pts for both biomarkers (GEP, n = 72, P = 0.007, ROC AUC 0.69; CPS, n = 96, P= 0.111, ROC AUC 0.58); biomarker data for all pts will be presented. ORR in the 110 pts with CPS ≥10% was 47% (95% CI, 38-57). Conclusions: Results confirm that pembro elicits clinically meaningful, durable responses in cisplatin-ineligible advanced UC. Consistent with PD-1 pathway biology, biomarkers (GEP and CPS) showed the expected trends of positive association with response to pembro. Pembro was well tolerated across cisplatin-ineligible pts, including elderly and pts with poor performance status. Clinical trial information: NCT02335424.
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284
Background: Treatment options are limited for patients (pts) with advanced urothelial cancer (UC) ineligible to receive cisplatin-based chemotherapy. Interim results from the first ...100 pts enrolled in the phase 2, open-label KEYNOTE-052 (ClinicalTrials.gov, NCT02335424) study suggested first-line pembrolizumab (pembro) had antitumor activity and acceptable safety in this pt population. Results from the fully enrolled study are presented. Methods: Key eligibility criteria included age ≥ 18 y, advanced UC of the renal pelvis, ureter, bladder, or urethra, cisplatin ineligibility (ECOG PS 2, creatinine clearance ≥ 30 to < 60 mL/min, grade ≥ 2 neuropathy or hearing loss, NYHA Class 3 heart failure), no prior systemic chemotherapy for advanced UC, measurable disease per RECIST v1.1, ECOG PS 0-2, and provision of a tumor sample for biomarker analyses. Pembro 200 mg was administered every 3 wk. Imaging was performed at wk 9, then every 6 wk for the first year, and every 12 wk thereafter. The primary end point was confirmed overall response rate (ORR; RECIST v1.1, independent review). Efficacy data are presented for pts with ≥ 4 mo follow-up, and safety data are presented for all pts. Results: In total, 370 pts were enrolled; median age was 74 y (range, 34-94 y); 42% had an ECOG PS 2. Reasons for cisplatin ineligibility included ECOG PS 2 (32%), renal dysfunction (49%), and both ECOG PS 2 and renal dysfunction (10%). ORR (95% CI) was 27% (22%-32%) among pts with ≥ 4 mo follow-up (n = 307); 6% of pts achieved a complete response. Among the ≥ 4 mo follow-up group, median (range) time to response was 2.0 (1.6-4.8) mo; median (range) duration of response was not reached (1+ to 14+ mo). 78% of responders had a response for ≥ 6 mo (KM estimate). PFS and OS rates at 6 mo were 31% and 67%, respectively (KM estimate). Any grade and grade ≥ 3 drug-related AEs occurred in 229 (62%) and 58 (16%) pts. 19 (5%) pts discontinued treatment because of a drug-related AE. Conclusions: Results from the fully enrolled KEYNOTE-052 study confirm that pembro elicits clinically meaningful and durable responses in cisplatin-ineligible pts with UC, including elderly pts and those with poor performance status. Clinical trial information: NCT02335424.
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