scholarly journals 345 Phase 3 study of combination pembrolizumab + olaparib therapy versus enzalutamide/abiraterone in metastatic castration-resistant prostate cancer (mCRPC) after progression on chemotherapy (KEYLYNK-010)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A370-A370
Author(s):  
Evan Yu ◽  
Se Hoon Park ◽  
Yi-Hsiu Huang ◽  
Mostefa Bennamoun ◽  
Lu Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Group Performance ◽  
Phase 3 ◽  
End Points ◽  
Link Type ◽  
Patient Reported ◽  
Pretreated Patients ◽  
Modified Recist ◽  
Docetaxel Chemotherapy

BackgroundCohort A of the phase 1b/2 KEYNOTE-365 study (NCT02861573) demonstrated promising antitumor activity with pembrolizumab + olaparib in patients with mCRPC unselected for homologous recombination deficiency. The prostate-specific antigen (PSA) and objective response rates (ORR) were both 9%, progression-free survival (PFS) was 4.3 months, overall survival (OS) was 14.4 months, and 12-month PFS and OS rates were 23.3% and 58.2%, respectively. The safety profile of the combination therapy was also aligned with the individual profiles of each agent. KEYLYNK-010 (NCT03834519) is a phase 3 trial to evaluate efficacy and safety of pembrolizumab + olaparib in molecularly unselected enzalutamide- or abiraterone-pretreated patients with mCRPC who progressed with docetaxel chemotherapy.MethodsEligibility criteria include histologically confirmed mCRPC unselected for homologous recombination repair (HRR) gene mutation, progression on docetaxel chemotherapy, progression on androgen deprivation therapy within 6 months before screening, received either abiraterone for metastatic castration-sensitive prostate cancer/mCRPC or enzalutamide for mCRPC (but not both) for ≥8 weeks (≥14 weeks with bone progression), and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients will also be required to provide tumor tissue for biomarker analysis. Approximately 780 adults will be randomized in a 2:1 ratio to pembrolizumab 200 mg IV Q3W (maximum 35 cycles) + olaparib 300 mg PO QD or abiraterone 1000 mg PO QD + prednisone or prednisolone 5 mg PO BID (enzalutamide-pretreated patients) or enzalutamide 160 mg PO QD (abiraterone-pretreated patients). Randomization will be stratified by prior treatment (abiraterone or enzalutamide) and measurable disease (yes/no). Treatment for all patients will continue until disease progression, unacceptable toxicity, or withdrawal. Response will be assessed by imaging (CT/MRI/bone) per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and then Q12W thereafter. The dual primary end points are radiographic PFS per PCWG3-modified RECIST v1.1, as assessed by BICR and OS. The key secondary end point is time to initiation of subsequent anticancer therapy or death. Other secondary end points include ORR, duration of response, time to PSA progression, time to first symptomatic skeletal-related event, and safety and tolerability. Patient-reported outcomes and identification of molecular biomarkers for treatment response are exploratory end points. KEYLYNK-010 is ongoing or planned in 19 countries across Asia, Australia, Europe, and North and South America.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov, NCT03834519Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

346 KEYNOTE-991: phase 3 study of pembrolizumab plus enzalutamide and androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (mHSPC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A371-A371
Author(s):  
Christian Gratzke ◽  
Christian Gratzke ◽  
Christian Gratzke ◽  
Cuizhen Niu ◽  
Christian Poehlein ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
The United States ◽  
Phase 3 ◽  
End Points ◽  
Once Daily ◽  
Link Type ◽  
Patient Reported ◽  
Biomarker Analysis ◽  
Modified Recist

BackgroundCombination of pembrolizumab, an anti–PD-1 antibody, added to enzalutamide, a nonsteroidal antiandrogen agent, has shown antitumor activity in abiraterone-resistant mCRPC (KEYNOTE-365, NCT02861573) and in patients with mCRPC for whom enzalutamide was ineffective (KEYNOTE-199, NCT02787005). These data indicate that the combination of pembrolizumab + enzalutamide with ADT warrants phase 3 evaluation. Also, efficacy in enzalutamide may be proimmunogenic, suggesting that it may be additive or synergistic in antitumor activity when combined with pembrolizumab.MethodsThe KEYNOTE-991 (NCT04191096) phase 3 trial will evaluate the efficacy and safety of enzalutamide + ADT (LHRH agonist/antagonist during study treatment or bilateral orchiectomy) + pembrolizumab or placebo in patients with mHSPC. Eligibility criteria include age ≥18 years, mHSPC, ≥2 bone lesions or visceral disease, no prior treatment with next-generation hormone agents, adequate organ function, and ECOG PS 0 or 1. Patients must provide tissue for biomarker analysis. Approximately 1232 patients will be randomized in a 1:1 ratio to receive enzalutamide 160 mg orally once daily + ADT + pembrolizumab 200 mg IV every 3 weeks (Q3W) or enzalutamide 160 mg orally once daily + ADT + placebo IV Q3W. Treatment will continue with pembrolizumab up to 35 cycles and treatment with enzalutamide will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). CT or MRI and radionuclide bone imaging will be used to assess response according to Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q12W from the date of randomization. Imaging will continue until the end of treatment and will resume Q12W during the posttreatment period. The co-primary end points are BICR-assessed radiographic PFS (according to PCWG3-modified RECIST v1.1) and OS. Key secondary end points are time to first subsequent anticancer therapy and time to symptomatic skeletal-related event. Other end points are PFS2 (progression after next line of therapy or death), PSA response rate, time to PSA progression, PSA undetectable rate, ORR, duration of response, time to soft tissue and radiographic bone progression per PCWG3-modified RECIST v1.1, safety, and patient-reported outcomes (eg, time to pain progression). Safety and tolerability will be evaluated using a tiered approach. KEYNOTE-991 is enrolling at 40 sites in Australia, Chile, Colombia, Israel, Japan, Poland, South Korea, Spain, Switzerland, Taiwan, and the United States.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov: NCT04191096Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

scholarly journals 425 Pembrolizumab + vibostolimab in patients with adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC) or treatment-emergent neuroendocrine mCRPC: phase 1b/2 KEYNOTE-365 cohorts G/H

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A455-A455
Author(s):  
Neal Shore ◽  
Johann De Bono ◽  
Gero Kramer ◽  
Anthony Joshua ◽  
Xin Tong Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Disease Progression ◽  
Response Rate ◽  
Group Performance ◽  
Neuroendocrine Cells ◽  
End Points ◽  
Link Type ◽  
Modified Recist ◽  
Phase 1B

BackgroundFrontline treatment for patients with adenocarcinoma mCRPC includes docetaxel, radium 223, or the next-generation hormonal agents (NHAs) abiraterone or enzalutamide. For patients with disease progression on these therapies, approximately 20% will develop treatment-emergent neuroendocrine mCRPC (t-NE) after diagnosis of prostate adenocarcinoma. The PD-1 inhibitor pembrolizumab showed antitumor activity when combined with olaparib in cohort A of the phase 1b/2 KEYNOTE-365 trial, and the TIGIT inhibitor vibostolimab showed antitumor activity in preclinical models. Combining PD-1 and TIGIT inhibition may have enhanced benefit in adenocarcinoma mCRPC or t-NE.MethodsKEYNOTE-365 is a nonrandomized, open-label, multicohort study (NCT02861573) to assess several pembrolizumab combination therapies in patient populations with adenocarcinoma mCRPC or t-NE. In each of cohorts G and H, 40–100 adults with Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1 who received docetaxel for mCRPC will be enrolled. Prior therapy with ≤2 NHAs and 1 other chemotherapy for adenocarcinoma mCRPC is permitted. Patients in cohort G must have adenocarcinoma of the prostate without small cell histology at study entry. Patients in cohort H must have t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review) that progressed within 6 months of starting an NHA for mCRPC or hormone-sensitive prostate cancer and progressed within 6 cycles of docetaxel for mCRPC. All patients will receive MK-7684A, a coformulation of pembrolizumab 200 mg and vibostolimab 200 mg intravenously every 3 weeks until disease progression, consent withdrawal, or other discontinuation event. Adverse events will be monitored through 30 days after discontinuation (90 days if serious) and graded per CTCAE v4.0. Computed tomography or magnetic resonance imaging will be performed at screening, every 9 weeks through week 54, and every 12 weeks thereafter. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are time to PSA progression, ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and overall survival.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT02861573Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

343 Phase 3 study of pembrolizumab + docetaxel and prednisone/prednisolone for metastatic castration-resistant prostate cancer (mCRPC) pretreated with next-generation hormonal agents (NHAs) (KEYNOTE-921)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A368-A368
Author(s):  
Daniel Petrylak ◽  
Neal Shore ◽  
Mostefa Bennamoun ◽  
Raffaele Ratta ◽  
Josep Piulats ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Response Rate ◽  
Abiraterone Acetate ◽  
Prior Treatment ◽  
Phase 3 ◽  
End Points ◽  
Link Type ◽  
Psa Response ◽  
Modified Recist

BackgroundCohort B of the phase 1b/2 KEYNOTE-365 study (NCT02861573) found that docetaxel + pembrolizumab + prednisone demonstrated activity in patients previously treated with abiraterone acetate or enzalutamide for mCRPC. The prostate-specific antigen (PSA) response rate was 28%; objective response rate (ORR) was 18% (7 partial responses); duration of response (DOR) was 6.7 months; progression-free survival (PFS) was 8.3 months; overall survival (OS) was 20.4 months; and the 12-month PFS and OS rates were 24.0% and 75.8%, respectively. The safety and tolerability profile of this combination was consistent with the profiles of each individual agent. The KEYNOTE-921 (NCT03834506) phase 3 trial will evaluate efficacy and safety of pembrolizumab + docetaxel + prednisone/prednisolone in patients with mCRPC after prior treatment with NHA.MethodsEligible patients are adults with histologically or cytologically confirmed mCRPC who experience disease progression with androgen deprivation therapy (or after bilateral orchiectomy) within 6 months of screening and have Eastern Cooperative Oncology Group performance status 0/1. Other eligibility criteria are disease progression or intolerance to NHA in the metastatic hormone-sensitive prostate cancer setting or CRPC setting, no prior treatment with chemotherapy for mCRPC, and tissue available for biomarker analysis. Treatment stratification factors are prior treatment with abiraterone acetate (yes or no) and metastases location (bone only, liver, other). Approximately 1000 patients will be randomly assigned to receive docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg orally BID and pembrolizumab 200 mg IV Q3W or docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg PO BID + placebo IV Q3W (1:1 ratio). Response and progression will be determined using imaging (CT/MRI/bone) according to PCWG3–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and Q12W thereafter. Treatment maximums are 10 cycles for docetaxel + prednisone/prednisolone and 35 cycles for pembrolizumab or placebo. Treatment discontinuation regardless of therapy received is mandated for disease progression, unacceptable toxicity, or consent withdrawal. The dual primary end points are radiographic PFS per PCWG3-modified RECIST v1.1, as assessed by BICR and OS, and the key secondary end point is time to initiation of subsequent anticancer therapy or death. Other secondary end points include PSA response rate, time to PSA progression, ORR, DOR, time to radiographic soft tissue progression, time to radiographic bone progression, and safety. KEYNOTE-921 is ongoing or planned in 22 countries across, Asia, Australia, Europe, and North and South America.ResultsN/AConclusionsN/AEthics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

344 Phase 3 trial of pembrolizumab and enzalutamide versus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) (KEYNOTE-641)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A369-A369
Author(s):  
Julie Nicole Graff ◽  
Joseph Burgents ◽  
Li Wen Liang ◽  
Arnulf Stenzl
Keyword(s):  
Response Rate ◽  
Objective Response ◽  
Abiraterone Acetate ◽  
Phase 3 ◽  
Once Daily ◽  
Link Type ◽  
Phase 2 Study ◽  
Psa Response ◽  
Pretreated Patients ◽  
Modified Recist

BackgroundAntitumor activity with pembrolizumab + enzalutamide was observed in cohort C of the phase 1b/2 KEYNOTE-365 (NCT02861573) study of abiraterone acetate–pretreated patients with mCRPC and in a phase 2 study (NCT02312557) of patients with mCRPC who experienced progression with enzalutamide alone. In KEYNOTE-365 cohort C, prostate-specific antigen (PSA) response rate was 22%, objective response rate (ORR) was 20%, and 12-month PFS and OS rates were 24.6% and 72.8%, respectively. Safety and tolerability of the combination was consistent with individual profiles of each agent. In the phase 2 study of enzalutamide-pretreated patients, 5 of 28 patients (18%) had a PSA decline of ≥50%, and 3 of 12 patients (25%) with measurable disease achieved objective response. KEYNOTE-641 (NCT03834493) is a randomized, phase 3 trial to assess efficacy and safety of pembrolizumab + enzalutamide versus placebo + enzalutamide in patients with mCRPC.MethodsEnrolled patients have biochemical or radiographic progression with androgen deprivation therapy/after bilateral orchiectomy within 6 months of screening, ECOG PS 0/1, ongoing androgen deprivation with serum testosterone <50 ng/dL, and tumor tissue availability for biomarker analysis. The study continues to enroll those who previously had abiraterone acetate therapy; the abiraterone-naive cohort is filled. Exclusion criteria are prior chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor. Treatment stratification factors are prior abiraterone acetate treatment (yes or no), metastases location (bone only or liver or other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes or no). Response and progression will be determined by imaging (CT/MRI/bone) per PCWG3–modified RECIST v1.1 on visits Q9W during the first year and Q12W thereafter. Approximately 1200 adults will be randomly assigned 1:1 in a double-blind fashion to receive enzalutamide 160 mg orally once daily + pembrolizumab 200 mg IV Q3W or enzalutamide 160 mg orally once daily + placebo for a maximum of 35 cycles or until disease progression, unacceptable toxicity, or consent withdrawal. Coprimary end points are radiographic PFS per PCWG3-modified RECIST v1.1, as assessed by blinded independent central review, and OS. The key secondary end point is time to subsequent anticancer therapy or death. Other secondary end points are ORR, DOR, PSA response rate, PSA undetectable rate, time to PSA progression, time to pain progression, time to symptomatic skeletal-related event, time to soft tissue progression, and safety. KEYNOTE-641 is ongoing or planned in 21 countries across Asia, Australia, Europe, and North and South America.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov, NCT03834493Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): KEYNOTE-991.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5595-TPS5595
Author(s):  
Christian Gratzke ◽  
Joseph E Burgents ◽  
Cuizhen Niu ◽  
Christian Heinrich Poehlein ◽  
Charles G. Drake
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Response Rate ◽  
Phase Iii ◽  
Antitumor Effects ◽  
End Points ◽  
Once Daily ◽  
Patient Reported ◽  
Biomarker Analysis ◽  
Modified Recist

TPS5595 Background: Pembro, an anti–PD-1 antibody, has shown antitumor activity as monotherapy and in combination with other agents in metastatic castration-resistant prostate cancer (mCRPC). As the antitumor effects of enza may be pro-immunogenic, we hypothesized that combining pembro and enza could show additive or synergistic antitumor activity. Furthermore, pembro + enza previously showed antitumor activity in pts with mCRPC for whom abiraterone failed (KEYNOTE-365, NCT02861573) and in pts with mCRPC for whom enza monotherapy failed (KEYNOTE 199, NCT02787005). These data warrant further evaluation of the combination of pembro + enza when given at the initiation of ADT. Methods: KEYNOTE-991 (NCT04191096) is a phase III trial to evaluate the efficacy and safety of enza + ADT + either pembro or placebo in patients with mHSPC. Approximately 1232 pts will be randomly assigned 1:1 to receive enza 160 mg orally once daily + ADT + pembro 200 mg IV every 3 weeks (Q3W) or enza 160 mg orally once daily + ADT + placebo IV Q3W. ADT is receipt of an LHRH agonist or antagonist during study treatment or bilateral orchiectomy. Treatment will be stratified by prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). Pts with mHSPC, with ≥2 bone lesions and/or visceral disease, who are naive to next-generation hormone agents, and who have ECOG PS 0 or 1 are eligible. Pts must provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q12W from the date of randomization. Treatment will continue with pembro for up to 35 cycles, and treatment with enza will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. Dual primary end points are radiographic progression-free survival (PFS) per PCWG3-modified RECIST v1.1 assessed by BICR and overall survival. Secondary end points are time to first subsequent anticancer therapy, time to symptomatic skeletal-related event, PFS2 (progression after next line of therapy or death), prostate-specific antigen (PSA) response rate, time to PSA progression, PSA undetectable rate, objective response rate, duration of response, and time to radiographic soft tissue progression. Other end points are safety and patient-reported outcomes (eg, time to pain progression). Clinical trial information: NCT04191096 .

318 Olaparib plus pembrolizumab in patients with previously treated advanced solid tumors with homologous recombination repair mutation and/or homologous recombination repair deficiency: KEYLYNK-007

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A344-A344
Author(s):  
Timothy A Yap ◽  
Mallika Dhawan ◽  
Andrew E Hendifar ◽  
Michele Maio ◽  
Taofeek K Owonikoko ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Homologous Recombination Repair ◽  
Advanced Solid Tumors ◽  
Repair Deficiency ◽  
Recombination Repair ◽  
Modified Recist ◽  
Previously Treated

BackgroundTreatment with the anti–PD-1 antibody pembrolizumab has improved clinical outcomes in multiple previously treated advanced solid tumors. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity as monotherapy in patients with previously treated advanced ovarian, breast, pancreatic, and prostate cancers with BRCA1/BRCA2 mutations (BRCAm). Activity was also seen in patients with previously treated advanced solid tumors with other homologous recombination repair mutation (HRRm) and in those with ovarian cancer with homologous recombination repair deficiency (HRD) phenotype. PARP inhibitors have been found to increase interferon signaling and tumor infiltrating lymphocytes, enhancing tumor susceptibility to immune checkpoint blockade. Antitumor activity of PD-(L)1 plus PARP inhibition was found to be higher than expected with either agent alone in patients with recurrent ovarian cancer regardless of BRCAm or HRD status and in patients with BRCAm breast cancer. KEYLYNK-007 (NCT04123366) evaluates the antitumor activity and safety of olaparib in combination with pembrolizumab in patients with previously treated advanced solid tumors with HRRm and/or HRD.MethodsThis phase 2, nonrandomized, multicenter, open-label study will enroll approximately 300 patients aged ≥18 years with histologically/cytologically confirmed, previously treated, advanced solid tumors with HRRm and/or HRD per Lynparza HRR-HRD assay (Foundation Medicine, Inc., Cambridge, MA, USA), with an ECOG PS of 0-1. Patients will be grouped by biomarker status: subgroup 1: BRCAm; subgroup 2: HRRm without BRCAm; and subgroup 3: HRD positive without HRRm (loss of heterozygosity score ≥16 per Lynparza HRR-HRD assay). Patients will receive olaparib 300 mg twice daily + pembrolizumab 200 mg intravenously Q3W (35 cycles) until PD, unacceptable AEs, intercurrent illness, investigator decision, withdrawal of consent, or pregnancy. Tumor imaging assessment by blinded independent central review (BICR) per RECIST v1.1 or Prostate Cancer Working Group (PCWG)–modified RECIST v1.1 for prostate cancer will occur Q9W for 12 months, then Q12W until PD, start of new anticancer treatment, withdrawal of consent, pregnancy, or death. AEs will be monitored throughout the study and for 30 days after final dose (90 days for serious AEs). The primary endpoint is ORR (RECIST v1.1 or PCWG–modified RECIST version 1.1 by BICR). Secondary endpoints include duration of response (DOR) and PFS (RECIST v1.1 or PCWG–modified RECIST v1.1 by BICR), OS, and safety. Point estimate and exact Clopper-Pearson CI for ORR, and Kaplan-Meier estimates for DOR, PFS, and OS will be calculated. A total of 89 sites are currently enrolling in 20 countries.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov identifier, NCT04123366Ethics ApprovalAn independent institutional review board or ethics committee approved the protocol at each study site, and the trial is being conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki.

scholarly journals 418 Phase 1b/2 KEYNOTE-365 cohort I: platinum-containing chemotherapy alone or in combination with pembrolizumab for treatment-emergent neuroendocrine prostate carcinoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A448-A448
Author(s):  
Johann De Bono ◽  
Neal Shore ◽  
Gero Kramer ◽  
Anthony Joshua ◽  
Xin Tong Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Carcinoma ◽  
Response Rate ◽  
Performance Status ◽  
Ecog Performance Status ◽  
End Points ◽  
Status Score ◽  
Modified Recist ◽  
Phase 1B ◽  
Performance Status Score

BackgroundTreatment-emergent neuroendocrine prostate carcinoma (t-NE) can occur de novo or after diagnosis of prostate adenocarcinoma. Treatment often includes platinum-containing chemotherapy because of t-NE’s histologic similarity to small cell lung cancer. The PD-1 inhibitor pembrolizumab has shown promising efficacy and acceptable safety when combined with olaparib, docetaxel, or enzalutamide for treatment of metastatic castration-resistant prostate cancer (mCRPC) in the multicohort phase 1b/2 KEYNOTE-365 study (NCT02861573). Cohort I will be used to compare platinum-containing chemotherapy alone with chemotherapy + pembrolizumab as treatment for t-NE.MethodsPatients who have t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review); experienced progression within 6 months of starting a next-generation hormonal agent (NHA) for mCRPC or hormone-sensitive prostate cancer and experienced progression within 6 cycles of docetaxel treatment for mCRPC; and have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 are eligible. Prior therapy with ≤2 NHAs and 1 other chemotherapy for mCRPC is permitted. Patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg IV on day 1 of each cycle every 3 weeks + carboplatin AUC of 5 IV on day 1 + etoposide 100 mg/m2 IV on days 1, 2, and 3 of each 21-day cycle for 4 cycles (arm 1) or the same chemotherapy regimen without pembrolizumab (arm 2); in each arm 40–100 patients will be enrolled. Pembrolizumab treatment will continue up to 2 years until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be stratified by ECOG performance status score (0 or 1). Computed tomography or magnetic resonance imaging will be performed every 9 weeks through week 54 and every 12 weeks thereafter. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are time to PSA progression; ORR and radiographic progression-free survival (PFS) per PCWG3-modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 by BICR and PCWG3-modified RECIST v1.1 by BICR; and overall survival. End points will be summarized for each arm without formal hypothesis testing.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT02861573Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

scholarly journals 417 Phase 3 study of pembrolizumab + belzutifan + lenvatinib or pembrolizumab/quavonlimab + lenvatinib versus pembrolizumab + lenvatinib as first-line treatment for advanced renal cell carcinoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A447-A447
Author(s):  
Toni Choueiri ◽  
Elizabeth Plimack ◽  
Thomas Powles ◽  
Martin Voss ◽  
Howard Gurney ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Antitumor Activity ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
End Points ◽  
Once Daily ◽  
Link Type ◽  
The World ◽  
First Line Treatment

BackgroundPembrolizumab + vascular endothelial growth factor (VEGF) inhibitor lenvatinib demonstrated antitumor activity as first-line treatment for advanced clear cell renal cell carcinoma (ccRCC) in phase 3 trial KEYNOTE-581/CLEAR (NCT02811861). Hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) showed antitumor activity in ccRCC, and a coformulation of pembrolizumab and CTLA-4 inhibitor quavonlimab (MK-1308A) showed antitumor activity in non–small cell lung cancer. HIF-2α or CTLA-4 inhibition with PD-1 and VEGF inhibition backbone combination may provide additional benefit as first-line treatment in ccRCC. This open-label, randomized, phase 3 study (NCT04736706) will be conducted to compare novel combination therapies pembrolizumab + belzutifan + lenvatinib (arm A) and MK-1308A + lenvatinib (arm B) with pembrolizumab + lenvatinib (arm C).MethodsApproximately 1431 adults with metastatic ccRCC, measurable disease per RECIST v1.1, and Karnofsky Performance Status Scale score ≥70% who had not previously undergone systemic therapy for advanced ccRCC will be enrolled. Patients will be randomly assigned 1:1:1 to arm A (belzutifan 120 mg + lenvatinib 20 mg oral once daily + pembrolizumab 400 mg IV every 6 weeks), arm B (MK-1308A [quavonlimab 25 mg + pembrolizumab 400 mg] IV every 6 weeks and lenvatinib 20 mg oral once daily), or arm C (pembrolizumab 400 mg IV every 6 weeks + lenvatinib 20 mg oral once daily). Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event; patients will receive pembrolizumab and MK-1308A for up to 18 cycles (approximately 2 years). Patients will be stratified by International mRCC Database Consortium (IMDC) score (favorable vs intermediate vs poor), region of the world (North America vs Western Europe vs rest of the world), and sarcomatoid features (yes vs no). Response will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review (BICR) at week 12 from randomization, every 6 weeks through week 78, and every 12 weeks thereafter. Adverse events and serious adverse events will be monitored throughout the study and for 90 days after treatment. Dual primary end points are progression-free survival per RECIST v1.1 by BICR and overall survival. Primary end points will be assessed in arm A compared with arm C and in arm B compared with arm C for patients with IMDC intermediate/poor status and in all patients regardless of IMDC status. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA,Eisai Inc., Woodcliff Lake, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT04736706Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

Sign in / Sign up

Export Citation Format

Share Document