Concurrent Pembrolizumab Research Articles

Final results of a phase I prospective trial evaluating the combination of stereotactic body radiotherapy (SBRT) with concurrent pembrolizumab in patients with metastatic non-small cell lung cancer (NSCLC) or melanoma.

9099Background: We report final Phase I results of a Phase I/II prospective trial assessing safety and tolerability of SBRT and concurrent pembrolizumab. Methods: Eligible patients had metastatic N...

Phase II multi-site investigation of neoadjuvant pembrolizumab and adjuvant concurrent radiation and pembrolizumab with or without cisplatin in resected head and neck squamous cell carcinoma.

6017Background: 2Despite aggressive adjuvant treatment, locally advanced HNSCC patients undergoing primary surgical resection with high risk [HR] features (extracapsular extension of lymph nodes (L...

Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment

BackgroundBrain metastases are common in patients with metastatic melanoma. With increasing numbers of melanoma patients on anti-PD-1 therapy, we sought to evaluate the safety and initial response of brain metastases treated with concurrent pembrolizumab and radiation therapy.MethodsFrom an institutional database, we retrospectively identified patients with melanoma brain metastases treated with radiation therapy (RT) who received concurrent pembrolizumab. Concurrent treatment was defined as RT during pembrolizumab administration period and up to 4 months after most recent pembrolizumab treatment. Response was categorized by change in maximum diameter on first scheduled follow-up MRI. Lesion and patient specific outcomes including response, lesion control, brain control and overall survival were recorded and descriptively compared to contemporary treatments with RT and concurrent ipilimumab or RT without immunotherapy.ResultsFrom January 2014 through December 2015, we identified 21 patients who received concurrent radiation therapy and pembrolizumab for brain metastases or resection cavities that had at least one scheduled follow-up MRI. Eleven underwent stereotactic radiosurgery (SRS), 7 received hypofractionated radiation and 3 had whole brain treatment (WBRT). All treatments were well tolerated with no observed Grade 4 or 5 toxicities; Grade 3 edema and confusion occurred in 1 patient treated with WBRT after prior SRS. For metastases treated with SRS, at first scheduled follow-up MRI (median 57 days post SRS), 70% (16/23) exhibited complete (CR, n = 8) or partial response (PR, n = 8). The intracranial response rates (CR/PR) for patients treated with SRS and concurrent ipilimumab and SRS without concurrent immunotherapy was 32% and 22%, respectively.ConclusionsConcurrent pembrolizumab with brain RT appears safe in patients with metastatic melanoma, and SRS in particular is effective in markedly reducing the size of brain metastases at the time of first follow-up MRI. These results compare favorably to SRS in combination with ipilimumab and SRS without concurrent immunotherapy.

A phase I/II trial of fixed-dose stereotactic body radiotherapy with sequential or concurrent pembrolizumab in metastatic urothelial carcinoma: evaluation of safety and clinical and immunologic response

BackgroundCurrent first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.1% in patients with progression or recurrence after platinum-based chemotherapy. Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment. These findings gave rise to the hypothesis that the combination of radiotherapy with anti-PD1 treatment could lead to a synergistic effect, hereby enhancing response rates.MethodsThe phase I part will assess the dose limiting toxicity of the combination treatment of stereotactic body radiotherapy (SBRT) with four cycles of pembrolizumab (200 mg intravenously, every 3 weeks) in patients with metastatic urothelial carcinoma. The dose of both pembrolizumab and SBRT will be fixed, yet the patients will be randomized to receive SBRT either before the first cycle of pembrolizumab or before the third cycle of pembrolizumab. SBRT will be delivered (24 Gy in 3 fractions every other day) to the largest metastatic lesion. Secondary objectives include response rate according to RECIST v1.1 and immune related response criteria, progression-free survival and overall survival. The systemic immune effect triggered by the combination therapy will be monitored on various time points during the trial. The PD-L1/TIL status of the tumors will be analyzed via immunohistochemistry and response rates in the subgroups will be analyzed separately. A Simon’s two-stage optimum design is used to select the treatment arm associated with the best response rate and with acceptable toxicity to proceed to the phase II trial. In this phase, 13 additional patients will be accrued to receive study treatment.DiscussionThe progress made in the field of immunotherapy has lead to promising breakthroughs in various solid malignancies. Unfortunately, the majority of patients do not respond. The current trial will shed light on the toxicity and potential anti-tumor activity of the combination of radiotherapy with anti-PD1 treatment and may identify potential new markers for response and resistance to therapy. Trial registration this trial is registered on clinicaltrials.gov (NCT02826564).

Initial Report on Safety and Lesion Response of Melanoma Brain Metastases After Stereotactic Radiosurgery or Hypofractionated Radiation Therapy in Patients Receiving Concurrent Pembrolizumab

Systemic treatment of metastatic melanoma (MM) increasingly involves pembrolizumab (pembro), a monoclonal antibody against the programmed death 1 (PD-1) receptor. MM patients with brain metastases often receive radiation treatment (RT) as stereotactic radiosurgery (SRS), but the efficacy and safety of concurrent pembro with SRS or other brain RT is unknown. We examined a single institution experience of SRS and hypofractionated RT with concurrent pembro in patients with melanoma brain metastases. From October 2007 to December 2015, 131 patients with MM underwent either SRS or hypofractionated RT for brain metastases. Systemic treatments at the time of brain RT were examined and follow-up MRIs analyzed for treatment response. Concurrent treatment was defined as RT occurring during pembro administration period or up to 4 months after most recent pembro treatment. Individual lesion response was categorized by change in maximum diameter of the lesion: complete response defined here as disappearance of lesion, partial response as >30% reduction, progression as >20% increase, and all other lesions defined as stable. Significant acute toxicities including hemorrhage were recorded. One hundred thirty-one patients with MM underwent SRS or hypofractionated radiation therapy to a total of 212 brain metastases (SRS = 169, hypofractionated = 43 lesions). Of these patients, 72 received either concurrent pembro (n = 19 patients; 31 lesions) or ipilimumab (ipi), a monoclonal antibody to cytotoxic T-lymphocyte antigen-4 (n = 53 patients; 89 lesions), while the remainder were on various agents including systemic chemotherapy or BRAF inhibitors, which serve here as a control for the concurrent immunotherapy groups (n = 59 patients; 92 lesions). Distribution of responses for treated lesions was significantly different in patients treated with concurrent pembro (CR = 33%,PR = 29%, stable = 33%, progressed = 4% at median 57 +/- 26 days) as compared to an equivalent number of lesions in concurrent ipi (CR = 13%, PR = 19%, stable = 66%, progressed 3% at median 53 +/- 11 days; P = 0.01) or control groups (CR = 3%, PR = 20%, stable = 70%, progressed, median 51 +/- 20 days; P < 0.01). There were no grade 3-4 acute toxicities including no hemorrhages from lesions treated with SRS and concurrent pembro in this early follow-up timeframe, similar to previous reports for ipi. Concurrent pembro with SRS appears to be safe and effective in rapidly reducing the size of melanoma brain metastases. We present here an initial report of these findings, as pembro becomes increasingly incorporated into treatment strategies for metastatic melanoma. Prospective data examining the effects of concurrent pembro with respect to longer term in-field and out-of-field recurrence free survival are required to evaluate these retrospective observations and further analyze the potentially synergistic effect of pembro with SRS.

Safety of immune checkpoint inhibitors in Chinese patients with melanoma.

This study aimed to determine the tolerability of Chinese melanoma patients, particularly those with hepatitis B virus (HBV) infection, to immune checkpoint inhibitor therapy. Patients with metastatic melanoma who received anti-cytotoxic T lymphocyte-associated antigen-4 antibody (ipilimumab) or anti-programmed death 1 antibody (pembrolizumab) therapy at our hospital between August 2012 and July 2015 were retrospectively reviewed. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Twenty-three patients with advanced melanoma were included; nine and 10 patients received infusions of ipilimumab and pembrolizumab, respectively, whereas four patients received concurrent ipilimumab and pembrolizumab therapy. There was no cessation of treatment because of agent-related adverse events in any patient. Immune-related adverse events were observed in 44% (4/9), 60% (6/10), 100% (4/4), and 61% (14/23) of patients receiving ipilimumab, pembrolizumab, concomitant ipilimumab and pembrolizumab, and any treatment, respectively. The most frequent immune-related adverse events were endocrine disorders (39%, 9/23), liver function abnormalities (22%, 5/23), and dermatological events (17%, 4/23). There were no gastrointestinal reactions. Toxicities were usually mild and easily managed; only 13% (3/23) of patients had grade 3 adverse events and none experienced grade 4 events or treatment-related death. No additional toxicity nor severe hepatotoxicity was observed in 11 patients who had previous HBV infection. The recommended anti-cytotoxic T lymphocyte-associated antigen-4 and anti-programmed death 1 antibody doses were well tolerated by Chinese patients. Thus, immune checkpoint inhibitors appear to be effective and safe in metastatic melanoma patients, including those with pre-existing HBV infection.