Dataset Information

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

ABSTRACT:

Importance

Consolidative programmed death ligand-1 (PD-L) inhibition after chemoradiotherapy improves overall survival and progression-free survival (PFS) for stage III non-small cell lung cancer (NSCLC) and requires safety evaluation for incorporation of programmed cell death 1 (PD-1) inhibition at the onset of chemoradiotherapy.

Objective

To determine the safety and tolerability of PD-1 inhibition concurrently with definitive chemoradiotherapy for NSCLC.

Design, setting, and participants

This phase 1 prospective multicenter nonrandomized controlled trial using a 3 plus 3 design was performed from August 30, 2016, to October 24, 2018, with a median follow-up of 16.0 (95% CI, 12.0-22.6) months and data locked on July 25, 2019. Twenty-one participants had locally advanced, unresectable, stage III NSCLC as determined by multidisciplinary review, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function. Data were analyzed from October 17, 2016, to July 19, 2019.

Interventions

Pembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Dose cohorts evaluated included full-dose pembrolizumab (200 mg intravenously every 3 weeks) 2 to 6 weeks after chemoradiotherapy (cohort 1); reduced-dose pembrolizumab (100 mg intravenously every 3 weeks) starting day 29 of chemoradiotherapy (cohort 2); full-dose pembrolizumab starting day 29 of chemoradiotherapy (cohort 3); reduced-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 4); and full-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 5). A safety expansion cohort of 6 patients was planned based on the maximum tolerated dose of pembrolizumab. Dose-limiting toxic effects were defined as pneumonitis of at least grade 4 within cycle 1 of pembrolizumab treatment.

Main outcomes and measures

Safety and tolerability of PD-1 inhibition with chemoradiotherapy for NSCLC. Secondary outcomes included PFS and pneumonitis rates.

Results

Among the 21 patients included in the analysis (11 female [52%]; median age, 69.5 [range, 53.0-85.0] years), no dose-limiting toxic effects in any cohort were observed. One case of grade 5 pneumonitis occurred in the safety expansion cohort with the cohort 5 regimen. Immune-related adverse events of at least grade 3 occurred in 4 patients (18%). Median PFS for patients who received at least 1 dose of pembrolizumab (n?=?21) was 18.7 (95% CI, 11.8-29.4) months, and 6- and 12-month PFS were 81.0% (95% CI, 64.1%-97.7%) and 69.7% (95% CI, 49.3%-90.2%), respectively. Median PFS for patients who received at least 2 doses of pembrolizumab (n?=?19) was 21.0 (95% CI, 15.3 to infinity) months.

Conclusions and relevance

These findings suggest that combined treatment with PD-1 inhibitors and chemoradiotherapy for stage III NSCLC is tolerable, with promising PFS of 69.7% at 12 months, and requires further study.

Trial registration

ClinicalTrials.gov Identifier: NCT02621398.

SUBMITTER: Jabbour SK

PROVIDER: S-EPMC7042914 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

Jabbour Salma K SK Berman Abigail T AT Decker Roy H RH Lin Yong Y Feigenberg Steven J SJ Gettinger Scott N SN Aggarwal Charu C Langer Corey J CJ Simone Charles B CB Bradley Jeffrey D JD Aisner Joseph J Malhotra Jyoti J

JAMA oncology 20200601 6

<h4>Importance</h4>Consolidative programmed death ligand-1 (PD-L) inhibition after chemoradiotherapy improves overall survival and progression-free survival (PFS) for stage III non-small cell lung cancer (NSCLC) and requires safety evaluation for incorporation of programmed cell death 1 (PD-1) inhibition at the onset of chemoradiotherapy.<h4>Objective</h4>To determine the safety and tolerability of PD-1 inhibition concurrently with definitive chemoradiotherapy for NSCLC.<h4>Design, setting, and ...[more]

PMID: 32077891

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Project description:ImportanceAdministration of pembrolizumab plus concurrent chemoradiation therapy (cCRT) may provide treatment benefit to patients with locally advanced, stage III non-small cell lung cancer (NSCLC).ObjectiveTo evaluate treatment outcomes and safety of pembrolizumab plus cCRT in stage III NSCLC.Design, setting, and participantsThe phase 2, nonrandomized, 2-cohort, open-label KEYNOTE-799 study enrolled patients between November 5, 2018, and July 31, 2020, from 52 academic facilities and community-based institutions across 10 countries. As of October 28, 2020, median (range) follow-up was 18.5 (13.6-23.8) months in cohort A and 13.7 (2.9-23.5) months in cohort B. Of 301 patients screened, 216 eligible patients with previously untreated, unresectable, and pathologically/radiologically confirmed stage IIIA/IIIB/IIIC NSCLC with measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) were enrolled.InterventionsPatients in cohort A (squamous/nonsquamous) received 1 cycle (3 weeks) of carboplatin (area under the curve [AUC] 6 mg/mL/min), paclitaxel (200 mg/m2), and pembrolizumab (200 mg), followed by carboplatin (AUC 2 mg/mL/min) and paclitaxel (45 mg/m2) once weekly for 6 weeks and 2 cycles of pembrolizumab plus standard thoracic radiotherapy. Patients in cohort B (nonsquamous) received 3 cycles of cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and pembrolizumab (200 mg) every 3 weeks and thoracic radiotherapy in cycles 2 and 3. Patients received 14 additional cycles of pembrolizumab.Main outcomes and measuresCoprimary end points were objective response rate per RECIST v1.1 by blinded independent central review and incidence of grade 3 to 5 pneumonitis.ResultsA total of 112 patients received treatment in cohort A (76 men [67.9%]; median [range] age, 66.0 [46-90] years; 66 patients [58.9%] with programmed cell death ligand 1 [PD-L1] tumor proportion score ≥1%) and 102 patients received treatment in cohort B (62 men [60.8%]; median [range] age, 64.0 [35-81] years; 40 patients [39.2%] with PD-L1 tumor proportion score ≥1%). Objective response rate was 70.5% (79 of 112; 95% CI, 61.2%-78.8%) in cohort A and 70.6% (72 of 102; 95% CI, 60.7%-79.2%) in cohort B. Median duration of response was not reached, but 79.7% and 75.6%, respectively, had response duration of 12 months or longer. Grade 3 or higher pneumonitis occurred in 9 of 112 patients (8.0%) in cohort A and 7 of 102 (6.9%) in cohort B. Grade 3 to 5 treatment-related adverse events occurred in 72 of 112 (64.3%) and 51 of 102 (50.0%) patients, respectively.Conclusions and relevanceThe findings of this phase 2, nonrandomized, 2-cohort study suggest promising antitumor activity of pembrolizumab plus cCRT and manageable safety in patients with previously untreated, locally advanced, stage III NSCLC.

Project description:PurposePembrolizumab is a humanized monoclonal antibody that blocks interaction between programmed death receptor-1 (PD-1) and its ligands (PD-L1, PD-L2). Although pembrolizumab is approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), its role in the management of locally advanced (LA) disease is not defined. We report a phase IB study evaluating the safety and efficacy of adding pembrolizumab to cisplatin-based chemoradiotherapy in patients with LA HNSCC.Patients and methodsEligible patients included those with oral cavity (excluding lip), oropharyngeal, hypopharyngeal, or laryngeal stage III to IVB HNSCC (according to American Joint Committee on Cancer, 7th edition, staging system) eligible for cisplatin-based, standard-dose (70 Gy) chemoradiotherapy. Pembrolizumab was administered concurrently with and after chemoradiotherapy with weekly cisplatin. Safety was the primary end point and was determined by incidence of chemoradiotherapy adverse events (AEs) and immune-related AEs (irAEs). Efficacy was defined as complete response (CR) rate on end-of-treatment (EOT) imaging or with pathologic confirmation at 100 days postradiotherapy completion. Key secondary end points included overall (OS) and progression-free survival (PFS).ResultsThe study accrued 59 patients (human papillomavirus [HPV] positive, n = 34; HPV negative, n = 25) from November 2015 to October 2018. Five patients (8.8%) required discontinuation of pembrolizumab because of irAEs, all of which occurred during concurrent chemoradiotherapy; 98.3% of patients completed the full planned treatment dose (70 Gy) of radiotherapy without any delays ≥ 5 days; 88.1% of patients completed the goal cisplatin dose of ≥ 200 mg/m2. EOT CR rates were 85.3% and 78.3% for those with HPV-positive and -negative HNSCC, respectively.ConclusionPembrolizumab in combination with weekly cisplatin-based chemoradiotherapy is safe and does not impair delivery of curative radiotherapy or chemotherapy in HNSCC. Early efficacy data support further investigation of this approach.

Project description:ImportanceAnthracycline-based therapy is standard first-line treatment for most patients with advanced and metastatic sarcomas. Although multiple trials have attempted to show improved outcomes in patients with soft-tissue sarcoma over doxorubicin monotherapy, each has fallen short of demonstrating improved outcomes.ObjectiveTo evaluate the safety and efficacy of doxorubicin in combination with pembrolizumab in patients with advanced, anthracycline-naive sarcomas.Design, setting, and participantsThis nonrandomized clinical trial used a 2-stage phase 2 design and was performed at a single, academic sarcoma specialty center. Patients were adults with good performance status and end-organ function. Patients with all sarcoma subtypes were allowed to enroll with the exception of osteosarcoma, Ewing sarcoma, and alveolar and embryonal rhabdomyosarcoma.InterventionsTwo dose levels of doxorubicin (45 and 75 mg/m2) were tested for safety in combination with pembrolizumab.Main outcomes and measuresObjective response rate (ORR) was the primary end point. Overall survival (OS) and progression-free survival (PFS) were secondary end points. Correlative studies included immunohistochemistry, gene expression, and serum cytokines.ResultsA total of 37 patients (22 men; 15 women) were treated in the combined phase 1/2 trial. The median (range) patient age was 58.4 (25-80) years. The most common histologic subtype was leiomyosarcoma (11 patients). Doxorubicin plus pembrolizumab was well tolerated without significant unexpected toxic effects. The ORR was 13% for phase 2 patients and 19% overall. Median PFS was 8.1 (95% CI, 7.6-10.8) months. Median OS was 27.6 (95% CI, 18.7-not reached) months at the time of this analysis. Two of 3 patients with undifferentiated pleomorphic sarcoma and 2 of 4 patients with dedifferentiated liposarcoma had durable partial responses. Tumor-infiltrating lymphocytes were present in 21% of evaluable tumors and associated with inferior PFS (log-rank P = .03). No dose-limiting toxic effects were observed.Conclusions and relevanceIn this nonrandomized clinical trial, doxorubicin plus pembrolizumab was well tolerated. Although the primary end point for ORR was not reached, the PFS and OS observed compared favorably with prior published studies. Further studies are warranted, especially those focusing on undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.Trial registrationClinicalTrials.gov Identifier: NCT02888665.

Project description:BackgroundThis study aims to investigate the efficacy and safety of postoperative intensity-modulated radiotherapy (IMRT) covering partial regional lymph node areas combined with chemotherapy for locally advanced thoracic esophageal squamous cell carcinoma patients.MethodsThis was a single-center, single-arm phase II clinical trial that began in 2014. Patients who underwent radical transthoracic resection within 3 months and were histologically confirmed esophageal squamous cell carcinoma (pT3-4 or N+, M0 determined according to AJCC Guidelines, Edition 7) were recruited. Postoperative radiotherapy was performed with a total dose of 50.4Gy in 28 fractions using IMRT. Clinical target volumes (CTVs) included tumor bed, anastomosis, bilateral supraclavicular region, and superior mediastinal lymph nodes. Synchronous chemotherapy for 2 cycles (paclitaxel 150mg/m2, day1; Cisplatin 25mg/m2, day1-3; every 4 weeks), followed by 2 cycles of consolidation chemotherapy with the same regimen. The primary endpoint was the 2-year local control rate, and the secondary endpoints were overall survival (OS) and adverse events (AEs).ResultsA total of 75 eligible patients were included from 2014 to 2017. The 2-year LRFS rate, as the primary endpoint, was 73.3%. The 1-year and 3-year OS rates were 88.0% and 68.0%, respectively. Local recurrence occurred in 13/75 (17.4%) patients, of which 2.7% (2/75) were extra-target lymph nodes. Grade 4 adverse events reported in this study included 10 cases (13.3%) of neutropenia, 1 case (1.3%) of anemia, and 2 cases (2.7%) of thrombocytopenia, without toxic-related deaths. Almost all (96%) patients completed the entire postoperative radiotherapy course, and 62 (82.7%) patients completed at least 2 cycles of chemotherapy.ConclusionPostoperative IMRT (clinical target volume including tumor bed, anastomosis, bilateral supraclavicular region, and superior mediastinal lymph nodes) combined with synchronous chemotherapy in patients with locally advanced thoracic esophageal squamous cell carcinoma was well tolerated, with a high local control rate and a low probability of recurrence outside the irradiation field.Clinical trial registrationhttps://clinicaltrials.gov/ChiCTR1900022689.

Project description:LESSONS LEARNED:Ramucirumab plus pembrolizumab revealed no unexpected safety findings in patients with advanced or metastatic biliary tract cancer, which is consistent with reports of other tumor cohorts within this phase Ia/b trial.Ramucirumab plus pembrolizumab did not demonstrate an improvement in overall survival when compared with historical controls in biomarker unselected, heavily pretreated patients with advanced or metastatic biliary tract cancer.Patients with programmed death-ligand 1 (PD-L1)-positive tumors had improved overall survival compared with patients with PD-L1-negative disease. BACKGROUND:Few treatment options exist for patients with advanced biliary tract cancer (BTC) following progression on gemcitabine-cisplatin. Preclinical evidence suggests that simultaneous blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) and programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) enhances antitumor effects. We assessed the safety and efficacy of ramucirumab, an IgG1 VEGFR-2 antagonist, with pembrolizumab, an IgG4 PD-1 antagonist, in biomarker-unselected patients with previously treated advanced or metastatic BTC. METHODS:Patients had previously treated advanced or metastatic adenocarcinoma of the gallbladder, intrahepatic and extrahepatic bile ducts, or ampulla of Vater. Ramucirumab 8 mg/kg was administered intravenously on days 1 and 8 with intravenous pembrolizumab 200 mg on day 1 every 3 weeks. The primary endpoint was safety and tolerability of the combination. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS:Twenty-six patients were treated at 12 centers in five countries. Hypertension was the most common grade 3 treatment-related adverse event (TRAE), occurring in five patients. One patient experienced a grade 4 TRAE (neutropenia), and no treatment-related deaths occurred. Objective response rate was 4%. Median progression-free survival and overall survival were 1.6 months and 6.4 months, respectively. CONCLUSION:Ramucirumab-pembrolizumab showed limited clinical activity with infrequent grade 3-4 TRAEs in patients with biomarker-unselected progressive BTC.

Project description:BackgroundIn the UK, chemotherapy is the standard treatment for inoperable, locally advanced, non-metastatic pancreatic cancer. Chemoradiotherapy is also an acceptable treatment option, for which gemcitabine, fluorouracil, or capecitabine can be used as concurrent chemotherapy agents. We aimed to assess the activity, safety, and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer.MethodsIn this open-label, randomised, two-arm, phase 2 trial, patients aged 18 years or older with histologically proven, locally advanced pancreatic cancer (with a tumour diameter of 7 cm or less) were recruited from 28 UK centres between Dec 24, 2009 and Oct 25, 2011. After 12 weeks of induction gemcitabine and capecitabine chemotherapy (three cycles of gemcitabine [1000 mg/m(2) on days 1, 8, 15 of a 28-day cycle] and capecitabine [830 mg/m(2) twice daily on days 1-21 of a 28-day cycle]), patients with stable or responding disease, tumour diameter of 6 cm or less, and WHO performance status 0-1 were randomly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine (300 mg/m(2) once per week) or capecitabine (830 mg/m(2) twice daily, Monday to Friday only), both in combination with radiation (50·4 Gy in 28 fractions). Randomisation (1:1) was done via a central computerised system and used stratified minimisation. The primary endpoint was 9-month progression-free survival, analysed by intention to treat including only those patients with valid CT assessments. This trial is registered with ISRCTN, number 96169987.Findings114 patients were registered and 74 were randomly allocated (38 to the gemcitabine group and 36 to the capecitabine group). After 9 months, 22 of 35 assessable patients (62·9%, 80% CI 50·6-73·9) in the capecitabine group and 18 of 35 assessable patients (51·4%, 39·4-63·4) in the gemcitabine group had not progressed. Median overall survival was 15·2 months (95% CI 13·9-19·2) in the capecitabine group and 13·4 months (95% CI 11·0-15·7) in the gemcitabine group (adjusted hazard ratio [HR] 0·39, 95% CI 0·18-0·81; p=0·012). 12-month overall survival was 79·2% (95% CI 61·1-89·5) in the capecitabine group and 64·2 (95% CI 46·4-77·5) in the gemcitabine group. Median progression-free survival was 12·0 months (95% CI 10·2-14·6) in the capecitabine group and 10·4 months (95% CI 8·9-12·5) in the gemcitabine group (adjusted HR 0·60, 95% CI 0·32-1·12; p=0·11). Eight patients in the capecitabine group had an objective response at 26 weeks, as did seven in the gemcitabine group. More patients in the gemcitabine group than in the capecitabine group had grade 3-4 haematological toxic effects (seven [18%] vs none, p=0·008) and non-haematological toxic effects (ten [26%] vs four [12%], p=0·12) during chemoradiation treatment; the most frequent events were leucopenia, neutropenia, and fatigue. Two patients in the capecitabine group progressed during the fourth cycle of induction chemotherapy. Of the 34 patients in the capecitabine group who received chemoradiotherapy, 25 (74%) received the full protocol dose of radiotherapy, compared with 26 (68%) of 38 patients in the gemcitabine group. Quality-of-life scores were not significantly different between the treatment groups.InterpretationOur results suggest that a capecitabine-based regimen might be preferable to a gemcitabine-based regimen in the context of consolidation chemoradiotherapy after a course of induction chemotherapy for locally advanced pancreatic cancer. However, these findings should be interpreted with caution because the difference in the primary endpoint was non-significant and the number of patients in the trial was small.FundingCancer Research UK.

Project description:ImportancePatients with oligometastatic non-small cell lung cancer (NSCLC) may benefit from locally ablative therapy (LAT) such as surgery or stereotactic radiotherapy. Prior studies were conducted before the advent of immunotherapy, and a strong biological rationale for the use of immunotherapy exists in a minimal residual disease state.ObjectiveTo evaluate whether the addition of pembrolizumab after LAT improves outcomes for patients with oligometastatic NSCLC.Design, setting, and participantsThis single-arm phase 2 trial of pembrolizumab therapy was performed from February 1, 2015, through September 30, 2017, at an academic referral cancer center. The 51 eligible patients enrolled had oligometastatic NSCLC (≤4 metastatic sites) and had completed LAT to all known sites of disease. Data were analyzed from February 1, 2015, to August 23, 2018.InterventionsWithin 4 to 12 weeks of completing LAT, patients began intravenous pembrolizumab therapy, 200 mg every 21 days, for 8 cycles, with provision to continue to 16 cycles in the absence of progressive disease or untoward toxic effects.Main outcomes and measuresThe 2 primary efficacy end points were progression-free survival (PFS) from the start of LAT (PFS-L), which preceded enrollment in the trial, and PFS from the start of pembrolizumab therapy (PFS-P). The study was powered for comparison with historical data on the first efficacy end point. Secondary outcomes included overall survival, safety, and quality of life as measured by the Functional Assessment of Cancer Therapy-Lung instrument.ResultsOf 51 patients enrolled, 45 (24 men [53%]; median age, 64 years [range, 46-82 years]) received pembrolizumab. At the time of analysis, 24 patients had progressive disease or had died. Median PFS-L was 19.1 months (95% CI, 9.4-28.7 months), significantly greater than the historical median of 6.6 months (P = .005). Median PFS-P was 18.7 months (95% CI, 10.1-27.1 months). Eleven patients died. Overall mean (SE) survival rate at 12 months was 90.9% (4.3%); at 24 months, 77.5% (6.7%). Neither programmed death ligand 1 expression nor CD8 T-cell tumor infiltration was associated with PFS-L. Pembrolizumab after LAT yielded no new safety signals and no reduction in quality of life.Conclusions and relevancePembrolizumab after LAT for oligometastatic NSCLC appears to improve PFS with no reduction in quality of life.Trial registrationClinicalTrials.gov identifier: NCT02316002.

Dataset Information

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

Importance

Objective

Design, setting, and participants

Interventions

Main outcomes and measures

Results

Conclusions and relevance

Trial registration

Publications

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

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