Real-World Experience of Pembrolizumab Monotherapy in Patients with Recurrent or Persistent Cervical Cancer: A Korean Multi-Center Retrospective Study (KGOG1041).
ABSTRACT: This study investigated the antitumor activity and safety of pembrolizumab in patients with recurrent cervical cancer in real-world practice. We conducted a multi-center retrospective study of patients with recurrent or persistent cervical cancer treated with pembrolizumab at sixteen institutions in Korea between January 2016 and March 2020. The primary endpoints were the objective response rate (ORR) and safety. Data were available for 117 patients. The median age was 53 years (range, 28-79). Sixty-four (54.7%) patients had an Eastern Cooperative Oncology Group (ECOG) performance status of ?2. Forty-nine (41.9%) patients were stage ?III at diagnosis. Eighty-eight (75.2%) patients had squamous cell carcinoma. The median number of prior chemotherapy lines was two (range, 1-6). During the median follow-up of 4.9 months (range, 0.2-35.3), the ORR was 9.4%, with three complete responses and eight partial responses. The median time to response was 2.8 months (range 1.3-13.1), and the median duration of response (DOR) was not reached. In the population of patients with favorable performance status (ECOG ?1) (n = 53), the ORR was 18.9%, and the median DOR was 8.9 months (range, 7.3-10.4). Adverse events occurred in 55 (47.0%) patients, including eight (6.8%) patients who experienced grade ?3 events, and two of them were suspicious treatment-related deaths. Pembrolizumab had modest antitumor activity in patients with recurrent cervical cancer comparable to that found in previously reported clinical trials. However, in patients with favorable performance status, pembrolizumab showed effective antitumor activity. Some safety profiles should be carefully monitored during treatment.
Project description:BACKGROUND:Pembrolizumab shows robust antitumor activity and favorable safety in metastatic melanoma. KEYNOTE-151 evaluated pembrolizumab in Chinese patients, who have more aggressive melanoma subtypes than other populations. METHODS:Chinese patients aged ≥18years with advanced melanoma previously treated with one line of therapy received pembrolizumab 2 mg/kg every 3 weeks for 35 cycles or until confirmed disease progression, intolerable toxicity, or study withdrawal. Primary end points were objective response rate (ORR) per RECIST v1.1 by blinded independent central review and safety. Key secondary end points included duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 and overall survival (OS). RESULTS:Median age was 52 years (N=103); 37.9% had acral and 14.6% had mucosal melanoma. Median follow-up was 7.9months at data cutoff (December 27, 2017). ORR was 16.7% (95% CI, 10.0-25.3%) (1 complete, 16 partial responses). Disease control rate was 38.2%. ORR was 15.8% for acral, 13.3% for mucosal melanoma. Median DOR was 8.4months; 65.6% of patients had response duration ≥6months. Median PFS was 2.8months (95% CI, 2.7-3.5months); 6-month rate was 20.4%. Median OS was 12.1months (95% CI, 9.6months-not reached); 6-month rate, 75.7%; 12-month rate, 50.6%. Treatment-related AEs (TRAEs) occurred in 87 (84.5%) patients; 9 (8.7%) experienced grade 3/4 TRAE and 2 (1.9%) discontinued because of TRAE; none died. Two deaths occurred that were unrelated to treatment. CONCLUSIONS:Pembrolizumab was well tolerated and provided clinically meaningful antitumor activity as second-line therapy in Chinese patients with advanced melanoma.
Project description:Interim results from the two-cohort, phase 2 KEYNOTE-100 study (NCT02674061) of 376 patients with previously treated advanced recurrent ovarian cancer (ROC) showed that pembrolizumab monotherapy was associated with an objective response rate (ORR) of 8.0% (95% CI, 5.4-11.2). We present outcomes for the Japanese patients (n = 21) enrolled in KEYNOTE-100. Patients with epithelial ROC had received either 1-3 prior chemotherapy lines and had platinum-free interval or treatment-free interval (PFI; TFI) of 3-12 months (cohort A) or 4-6 prior chemotherapy lines and had PFI/TFI of ?3 months (cohort B). All patients received pembrolizumab 200 mg every 3 weeks as monotherapy for 2 years or until progression, death, unacceptable toxicity or consent withdrawal. Primary objectives were ORR per RECIST v1.1 for each cohort and higher programmed death ligand-1 (PD-L1) tumor expression. The relationship between PD-L1 expression (measured as combined positive score [CPS]) and ORR was assessed. Twenty-one Japanese patients (cohort A, n = 19; cohort B, n = 2) were treated. The median (range) age was 57 (37-78) years; 19 (90.5%) patients had ECOG status of 0 and 16 (76.2%) patients had stage III-IV disease. ORR was 19.0% (95% CI, 5.4-41.9) and seemed to increase with increasing PD-L1 expression. A total of 13 (61.9%) patients had treatment-related adverse events (TRAE), and 5 (23.8%) had grade 3-4 TRAE. There were no treatment-related deaths in this subpopulation. Pembrolizumab monotherapy was associated with antitumor activity in Japanese patients with ROC, with no new safety signals identified in this subpopulation. The data suggested a trend toward higher PD-L1 expression among some patients with higher ORR.
Project description:PURPOSE:We evaluated the efficacy and safety of pembrolizumab in patients with recurrent gynecologic cancers in real-world practice. MATERIALS AND METHODS:We conducted a retrospective, single-institution study of patients with recurrent gynecologic malignancies treated with pembrolizumab. The primary endpoints were the objective response rate (ORR) and safety. RESULTS:Thirty-one patients treated with pembrolizumab were included. The primary disease sites were the uterine cervix (n=18), ovaries (n=8), and uterine corpus (n=5). Fifteen of the 31 patients (48%) had an Eastern Cooperative Oncology Group performance status of ?2. The median number of prior chemotherapy lines was 2 (range, 1-6), and 14 of 31 patients (45%) had received ? 3 prior lines of chemotherapy. The overall ORR was 22.6%: specifically, 22.3% (4 of 18 patients), 12.5% (1 of 8 patients), and 40% (2 of 5 patients) for cervical, ovarian, and endometrial cancers, respectively. During a median follow-up of 4.7 months (range, 0.2-35.3), the median time to response was 1.9 months (range, 1.4-5.7). The median duration of response was not reached (range, 8.8-not reached). The median progression-free survival was 2.5 months (95% confidence interval, 1.7-not reached). Adverse events occurred in 20 patients (64.5%), and only 3 (9.7%) were grade ?3. There was one case of suspicious treatment-related mortality, apart from which most adverse events were manageable. CONCLUSION:In real-world practice, pembrolizumab was feasible and effective in heavily treated recurrent gynecologic cancer patients with poor performance status who may not be eligible for enrollment in clinical trials.
Project description:KEYNOTE-012 was a phase Ib, multicohort study designed to investigate efficacy and safety of pembrolizumab in advanced solid tumors. Results from the subset of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) from the Asia-Pacific region are reported. Patients with recurrent/metastatic HNSCC, measurable disease (RECIST version 1.1), and ECOG performance status (PS) 0-1 were eligible for enrollment in the HNSCC expansion cohort. Patients received pembrolizumab 200 mg every 3 weeks. Response was assessed every 8 weeks. Co-primary end-points were safety and overall response rate (RECIST version 1.1, central review). Secondary end-points included overall survival and response duration. Patients enrolled at any of the five centers throughout the Asia-Pacific region were included in these analyses. Twenty-six patients with HNSCC from the Asia-Pacific region received pembrolizumab. The median age was 62 years, 65% of patients had ECOG PS 1, and 62% had received two or more prior therapies for recurrent/metastatic disease. Sixteen (62%) patients experienced a treatment-related adverse event of any grade, including two (8%) patients who experienced one or more events of grade 3 severity. No treatment-related deaths occurred. The overall response rate was 19% (95% confidence interval, 7%-39%). After a median follow-up of 12 months (range, 2-21 months), a median response duration was not reached (range, 6 to 17+ months); four of five responses lasted ?6 months. Median overall survival was 11.6 months (95% confidence interval, 4.7-17.7 months). Pembrolizumab was well tolerated and had durable antitumor activity in patients with HNSCC from the Asia-Pacific region. (Trial registration no. NCT01848834.).
Project description:BACKGROUND:Mucosal melanoma is an aggressive melanoma with poor prognosis. We assessed efficacy of pembrolizumab in patients with advanced mucosal melanoma in KEYNOTE-001 (NCT01295827), -002 (NCT01704287), and -006 (NCT01866319). METHODS:Patients received pembrolizumab 2?mg/kg every 3 weeks (Q3W) or 10?mg/kg Q2W or Q3W. Response was assessed by independent central review per RECIST v1.1. RESULTS:1567 patients were treated and 84 (5%) had mucosal melanoma. Fifty-one of 84 were ipilimumab-naive. In patients with mucosal melanoma, the objective response rate (ORR) was 19% (95% CI 11-29%), with median duration of response (DOR) of 27.6 months (range 1.1?+?to 27.6). Median progression-free survival (PFS) was 2.8 months (95% CI 2.7-2.8), with median overall survival (OS) of 11.3 months (7.7-16.6). ORR was 22% (95% CI 11-35%) and 15% (95% CI 5-32%) in ipilimumab-naive and ipilimumab-treated patients. CONCLUSION:Pembrolizumab provides durable antitumour activity in patients with advanced mucosal melanoma regardless of prior ipilimumab.
Project description:On August 5, 2016, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA injection, Merck Sharp & Dohme Corp., Kenilworth, NJ) for treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. Approval was based on the objective response rate (ORR) and duration of response (DoR) in a cohort of patients in a nonrandomized multi-cohort trial (KEYNOTE-012) that included 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy. Patients received either intravenous pembrolizumab 10 mg/kg every 2 weeks or 200 mg every 3 weeks. ORR was determined by independent review according to Response Evaluation Criteria in Solid Tumors 1.1. ORR was 16% (95% confidence interval 11, 22) with a complete response rate of 5%. DoR ranged from 2.4+ months to 27.7+ months. Twenty-three of 28 responding patients (82%) had response durations of ?6 months. Safety was evaluated in 192 patients with HNSCC receiving at least one dose of pembrolizumab. Frequent (?2%) serious adverse reactions were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes mellitus, skin toxicity, myositis, and thyroid disorders. The benefit-risk profile of pembrolizumab was considered acceptable in this patient population. As a condition of accelerated approval, Merck is required to conduct a confirmatory trial; this trial, KEYNOTE-040, is ongoing. IMPLICATIONS FOR PRACTICE:This accelerated approval expands the U.S. Food and Drug Administration-approved indications for pembrolizumab, providing health care providers with new information regarding pembrolizumab for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. Pembrolizumab is the first drug to receive approval for treatment of patients with HNSCC since cetuximab was approved for this indication in 2006.
Project description:PURPOSE:Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors. METHODS:Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORRWk24); secondary efficacy end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor assessments were evaluated by investigators per immune-related RECIST. RESULTS:At data cutoff, 108 patients with previously treated endometrial carcinoma were enrolled, with a median follow-up of 18.7 months. The ORRWk24 was 38.0% (95% CI, 28.8% to 47.8%). Among subgroups, the ORRWk24 (95% CI) was 63.6% (30.8% to 89.1%) in patients with microsatellite instability (MSI)-high tumors (n = 11) and 36.2% (26.5% to 46.7%) in patients with microsatellite-stable tumors (n = 94). For previously treated patients, regardless of tumor MSI status, the median DOR was 21.2 months (95% CI, 7.6 months to not estimable), median PFS was 7.4 months (95% CI, 5.3 to 8.7 months), and median OS was 16.7 months (15.0 months to not estimable). Grade 3 or 4 treatment-related adverse events occurred in 83/124 (66.9%) patients. CONCLUSION:Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile.
Project description:Purpose Treatment with pembrolizumab, an anti-programmed death-1 antibody, at 10 mg/kg administered once every 2 weeks, displayed durable antitumor activity in programmed death-ligand 1 (PD-L1) -positive recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results from the expansion cohort, in which patients with HNSCC, irrespective of biomarker status, received a fixed dose of pembrolizumab at a less frequent dosing schedule, are reported. Patients and Methods Patients with R/M HNSCC, irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200 mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary end points were overall response rate (ORR) per central imaging vendor (Response Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points included progression-free survival, overall survival, and association of response and PD-L1 expression. Patients who received one or more doses of pembrolizumab were included in analyses. Results Of 132 patients enrolled, median age was 60 years (range, 25 to 84 years), 83% were male, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of response was not reached (range, ? 2 to ? 11 months). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1-positive versus -negative patients (22% v 4%; P = .021). Treatment-related adverse events of any grade and grade ? 3 events occurred in 62% and 9% of patients, respectively. Conclusion Fixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC.
Project description:Importance:Poly(adenosine diphosphate-ribose) polymerase inhibitor and anti-programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC). Objective:To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC. Design, Setting, and Participants:This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019. Interventions:Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. Main Outcomes and Measures:The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival. Results:Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n = 47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected. Conclusions and Relevance:Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation. Trial Registration:ClinicalTrials.gov identifier: NCT02657889.
Project description:Importance:Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. Objective:To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. Design, Setting, and Participants:The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to ?23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. Interventions:The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. Main Outcomes and Measures:The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. Results:Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ?14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. Conclusions and Relevance:Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy. Trial Registration:ClinicalTrials.gov identifier: NCT02657889.