Cycles Of Pembrolizumab Research Articles

Abstract B072: Immune checkpoint blockade enhances mutated calreticulin-induced T-cell immunity in myeloproliferative neoplasms

Abstract Somatic mutations in the CALR gene are key drivers of cellular transformation in myeloproliferative neoplasms (MPN) and are the second most common driver mutations in essential thrombocythemia (ET) and myelofibrosis (MF) patients. CALR mutations are 1-bp frameshift mutations that result in the formation of a novel C-terminus with an identical 36-amino acid (aa) sequence that is shared by all CALR+ MPN patients. We hypothesized that the recurrence and uniformity of the novel C-terminus mark the mutated (mut)-CALR an attractive candidate as an MPN-specific tumor neoantigen that might elicit anti-tumor immune responses across patients who express this mutation. To assess the immunogenicity of mut-CALR neopeptide, we interrogated the binding affinity of epitopes from the altered C-terminus using in silico peptide binding prediction algorithms. The analysis showed that multiple epitopes could bind to class I and II human leukocyte antigens (HLA). We investigated whether we could elicit T-cell responses against mut-CALR neopeptide from CALR+ MPN patients. Peripheral blood mononuclear cells (PBMCs) from 18 MPN patients with ET (7), MF (4) or MF arising from ET (7) were stimulated in vitro with pooled overlapping long peptides (OLPs; 14-15 aa) spanning the mutated or wild type (WT) CALR C-terminus and T-cell responses were assessed by enzyme-linked immunospot assay (ELISPOT). There was a significant increase in interferon (IFN)-γ production upon stimulation with mut-CALR OLPs, whereas the corresponding WT sequence did not induce a T-cell response. Next, we evaluated whether mut-CALR-specific T-cells were undergoing exhaustion. Examination of the expression of checkpoint receptors on T-cells ex vivo determined that T-cells from peripheral blood of CALR+ MPN patients exhibited increased expression of multiple cell surface inhibitory molecules compared to healthy donor T-cells, including programmed cell death (PD)-1 and cytotoxic T lymphocyte-associated antigen (CTLA)-4. In order to address whether PD-1 and CTLA-4 overexpression suppressed mut-CALR-specific T-cell responses in CALR+ MPN patients, PD-1 or CTLA-4 signaling on T-cells was blocked through addition of monoclonal blocking antibodies. T-cell responses against mut-CALR peptides were recovered in 3 CALR+ MPN patients that were previously nonresponsive to mut-CALR stimulation. To gain further insights into checkpoint receptor-mediated T-cell suppression in CALR+ MPN patients, we investigated mut-CALR-specific T-cell responses in a CALR+ MPN patient receiving PD-1 inhibitor pembrolizumab, in our ongoing clinical trial (NCT03065400). We monitored the changes in the frequencies of peripheral blood T-cells in this patient before and after pembrolizumab treatment by both flow cytometry and T-cell receptor (TCR) sequencing. Prior to therapy, this patient had low proportion of T-cells (4.33% of PBMCs) and 32.3% of the T-cells expressed PD-1. After 2 cycles of pembrolizumab, the T-cell proportion greatly increased (26% of PBMCs) and remained high when measured after 6 cycles (18% of PBMCs). Sequencing of TCR Vβ chains of peripheral blood T-cells revealed that T-cells exhibited greater clonality after pembrolizumab treatment. Furthermore, we evaluated changes in mut-CALR-specific T-cell responses in this CALR+ MPN patient prior to and during pembrolizumab administration. At baseline, peripheral blood T-cells from this patient did not respond to stimulation with mut-CALR peptides. After pembrolizumab treatment, however, mut-CALR-specific T-cell responses were evident, as shown by increased IFN-γ production. Together, these results establish mut-CALR as a novel MPN-specific tumor shared-neoantigen and provide a strong rationale to study its immunogenic properties to inform the design of novel immunotherapies targeting mut-CALR in MPN patients carrying the mutation. Citation Format: Cansu Cimen Bozkus, Vladimir Roudko, John P. Finnigan, John Mascarenhas, Ronald Hoffman, Camelia Iancu-Rubin, Nina Bhardwaj. Immune checkpoint blockade enhances mutated calreticulin-induced T-cell immunity in myeloproliferative neoplasms [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B072.

Relapsed Diffuse Large B-Cell Lymphoma after Allogeneic CAR T-Cell Therapy Successfully Treated with PD1 Inhibition

Introduction Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) post-chimeric antigen receptor therapy (CAR-T) are limited. Here, we report the successful treatment of R/R DLBCL with programmed cell death 1 (PD1) inhibition post-allogeneic CAR-T. Case Report A previously healthy 26-year-old Caucasian man developed B-symptoms and cervical lymphadenopathy. Biopsy revealed DLBCL, activated B-cell subtype, double expressor and Ki-67 >80%. PET/CT scan revealed disease above and below the diaphragm. He achieved a partial response (PR) after R-CHOP, progressive disease (PD) after R-ICE, stable disease (SD) after R-ESHAP, and PD one month after autologous CD19-targeted CAR-T with CTL019 (CD3ζ/4-1BB). He then received R-lenalidomide (len) with radiation (24 Gy) to his mediastinal mass achieving a PR, followed by a myeloablative (Cy/TBI-12 Gy) allogeneic stem cell transplant (aSCT) from his 10/10 HLAmatched brother. He achieved 100% donor chimerism 30 days post-aSCT (D+30). Despite persistent full donor chimerism, D+60 PET/CT showed PD with confirmed relapse upon biopsy. Immunosuppression was discontinued, and ibrutinib with len was started, followed by donor lymphocyte infusion (DLI) which led to a mixed response. He then continued on ibrutinib with weekly temsirolimus and received a second DLI achieving a PR, with PD shortly thereafter. He next proceeded to allogeneic CAR-T with axicabtagene-ciloleucel (CD3ζ/CD28), complicated by grade 1 cytokine release syndrome without neurotoxicity. Three weeks post-CAR-T, he developed diplopia due to a cranial nerve palsy. Brain MRI showed new pontine T2 changes. Cerebrospinal fluid (CSF) was negative for lymphoma and infection, but notable for T-cell predominance. One month postCAR-T, PET/CT showed a complete metabolic response (CMR). Repeat brain MRI was unchanged. Two months later, he developed dizziness and intractable nausea, and repeat brain MRI showed a new lesion in the inferior cerebellar vermis, with resolution of previous pontine change. Evaluation of the CSF and peripheral blood revealed no CAR T-cell persistence, and PET/CT confirmed disease relapse in the cerebellum and mediastinum. Patient then received focal radiation (24 Gy) to his cerebellar lesion along with pembrolizumab 200 mg IV every 3 weeks, after which his neurologic symptoms resolved. MRI one day after radiation showed near-complete resolution of enhancing vermis lesion. After 3 cycles of pembrolizumab, PET/CT showed a CMR, with no active disease on brain MRI. Three months into PD1-inhibition therapy, his disease remains in CMR, without GVHD nor treatment-related toxicities. Conclusion This case illustrates the efficacy of allogeneic CAR-T after failure of autologous CAR-T and aSCT. Furthermore, PD1 inhibition can be used safely after allogeneic CAR-T, underscoring the need for prospective clinical studies.

Efficacy, safety, and resistance profile of osimertinib in T790M mutation-positive non-small cell lung cancer in real-world practice.

The efficacy and safety of osimertinib were demonstrated in clinical trials; however, real-world clinical data, particularly the resistance profile, are limited. Here, we investigated the efficacy, safety, and resistance profile of osimertinib in real-world practice. We reviewed medical records of T790M mutation-positive lung cancer patients who started osimertinib between February 2016 and June 2017. Molecular pathologic data of biopsy samples obtained after acquisition of resistance to osimertinib were also analyzed. The study included 23 patients with a median age of 59 years. The median follow-up duration was 11.9 months (IQR, 4.7–15.8). Objective response was achieved in 17 (73.9%) patients, and the disease was controlled in 22 (95.7%) patients. Median progression-free survival (PFS) was 7.4 months (95% CI, 3.6–11.0). Adverse events were minimal except for one case of pneumonitis. Of 14 patients experiencing disease progression, 10 underwent re-biopsy. The T790M mutation disappeared in seven patients (70%), and one showed wild-type conversion. PFS was shorter in the T790M-loss group than in the T790M-persistent group (4.4 vs. 7.7 months). Two patients with small cell transformation responded well to subsequent chemotherapy. One patient developed a C797S mutation that became undetectable after two cycles of gemcitabine and cisplatin followed by six cycles of pembrolizumab, after which the patient responded well to osimertinib. In conclusion, osimertinib showed favorable efficacy and safety in real-world practice comparable to those observed in clinical trials. Repeat biopsy after the acquisition of resistance to osimertinib is helpful to direct further treatment strategies.

Pembrolizumab Plus Chemotherapy as Neoadjuvant Treatment for Locally Advanced Triple-Negative Breast Cancer: Results from the Phase 1b Open-Label, Multicohort KEYNOTE-173 Study

Background: The phase 1b KEYNOTE-173 study assessed the safety and preliminary antitumour activity of neoadjuvant chemotherapy plus pembrolizumab in locally advanced non-metastatic triple-negative breast cancer (TNBC). Methods: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A–F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), followed by 8 cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks and then doxorubicin and cyclophosphamide for additional 12 weeks before surgery. Primary endpoints were safety and recommended phase 2 dose (RP2D); secondary endpoints were pathological complete response (pCR) rate, objective response rate (ORR), event-free and overall survival. Exploratory endpoints included the relationship between outcome and potential biomarkers, such as tumour programmed death ligand 1 (PD-L1) expression (combined positive score [CPS]) and stromal tumour-infiltrating lymphocyte levels (sTILs). Study is registered with ClinicalTrials.gov, NCT02622074. Findings: Sixty patients were enrolled between February 18, 2016 and February 28, 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n=9 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold, whereas 2 cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%), which were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range, 30%–80%). 12-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 CPS, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). Interpretation: The combination of neoadjuvant chemotherapy with pembrolizumab for locally advanced TNBC showed manageable toxicity and promising antitumour activity. In an exploratory analysis, pCR rate showed positive correlation with tumour PD-L1 expression and sTIL levels. Funding: Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Declaration of Interest: PS has received grants from AstraZeneca, Roche, Genentech, Oncogenex, Novartis, Astellas and consulting fees from Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, and Puma Biotechnology. His spouse has received consulting fees from Genentech and Roche. RS received research support for the scoring of sTILs presented in this manuscript. YHP has received grants, personal fees and non-financial support from Pfizer, Eisai, and Roche, personal fees and nonfinancial support from Merck, grants and personal fees from Novartis, personal fees from Celgene, and non-financial support from Hanmi. SBK has received grants from Novartis, Sanofi-Aventis, Kyowa-Kirin Inc, and DongKook Pharm Co and has received consulting fees from Novartis, AstraZeneca, Lilly, Enzychem, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, and Daiichi-Sankyo. JS has received grants from Merck, Roche, Novartis, AstraZeneca, Lilly, Pfizer, Bayer, GlaxoSmithKline, CONTESSA, and Daiichi Sankyo. TF has received grants and consulting fees (as institutional payments) from Pfizer, grants from Roche, and royalties for authorship from Wolters Kluwer Health (UpToDate). SK has received personal fees from Roche, Genomic Health, Lilly, Novartis, Amgen, Celgene, Daiichi Sankyo, AstraZeneca, Somatex, Merck, Pfizer, Puma Biotechnology, and PFM Medical and non-financial support from Roche and Daiichi Sankyo. RD has received personal fees from AstraZeneca, Eisai, Lilly, Merck, Novartis, Pfizer, Roche, and Seattle Genetics. JC has received grants (as institutional payments) from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, Merck, Pfizer, Piqur Therapeutics, Puma Biotechnology, Queen Mary University of London, and Seagen, consulting fees from Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck, GlaxoSmithKline, and Leuko, and honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck, and Daiichi Sankyo. SL has received grants (as institutional payments) from Novartis, Bristol-Myers Squibb, Merck, Roche-Genentech, Puma Biotechnologyand Eli Lilly, has acted as a consultant (not compensated) for Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and Roche-Genentech and has received consulting fees (to institution) from Aduro Biotech. EMC has nothing to disclose. LY, AW, KT, and VK are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Ethical Approval: The study protocol was approved by the appropriate institutional review board or independent ethics committee at each participating institution. The study was conducted in accordance with the protocol, good clinical practice guidelines, provisions of the Declaration of Helsinki and all local regulations. All patients provided written informed consent to participate.

A Phase II Study of Sequential Pembrolizumab (PEM) Followed By AVD for Frontline Treatment of Classical Hodgkin Lymphoma (CHL): Quantifying Response Following PEM Monotherapy with FDG-PET-Derived Metabolic Tumor Volume and Total Lesion Glycolysis

Background:Pembrolizumab (PEM), a PD-1 inhibitor, is US FDA approved for the treatment of relapsed/refractory cHL based on results of a pivotal trial demonstrating an overall response rate of 69% and complete response (CR) rate of 22%. We hypothesized that PEM monotherapy would result in a higher CR rate (50%) in previously untreated patients owing to greater immunocompetence. Consequently, we initiated a phase 2 clinical trial of upfront sequential PEM and AVD (Adriamycin, Vinblastine, Dacarbazine) chemotherapy. While several of the initial patients had dramatic responses to PEM x's 3 on PET2, they only met Lugano criteria for partial responses. In an attempt to better reflect and quantify the response to checkpoint inhibition, we amended our protocol to include additional analysis of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) which have been investigated as predictors of response in cHL and DLBCL. Herein, we report an interim analysis of toxicity and efficacy, measured by Deauville score, MTV and TLG in the first 13 patients to complete PEM monotherapy.Methods:Patients ≥ 18 years of age with newly diagnosed cHL stages I-IV, including unfavorable early stage disease with at least one risk factor according to the NCCN criteria, were eligible. Patients had a pre-therapy PET-CT, followed by 3 cycles of PEM at 200 mg every 3 weeks and interim PET-CT (PET2) after single agent PEM for primary analysis. Subsequently, patients received 4-6 cycles of AVD chemotherapy based on initial stage. MTV representing the total volume of the metabolically active tumor in a volume of interest (VOI) was calculated using the fixed 41% SUVmax threshold corresponding to the dimensions of the tumor. TLG, combining the volumetric and metabolic information of FDG-PET, was calculated by multiplying the SUVmean of the segmented VOI and the MTV. These measurements were performed using SyngoVia software, Multi-foci segmentation tool (Siemens). Blinded central review of the visually assessed Deauville score was performed, and if different from the report by one of four nuclear medicine radiologists, a second central review was performed to adjudicate. Correlative studies include serum and biopsy samples pre/post PEM to assess immune biomarkers of response.Results:Fifteen patients were enrolled from September 2017, through a data cut off of July 10, 2018, at Northwestern University. Thirteen patients have completed lead-in PEM monotherapy and have undergone PET2. Median age was 30 years (range, 23-77). Eight patients had unfavorable early stage disease and 7 had advanced stage. Early stage risk factors included bulky disease (n=8), B-symptoms (n=5), and elevated ESR (n=5). Overall, therapy was well tolerated. Grade 3 events included lymphopenia (n=1) and diarrhea (n=1). Only one grade 4 immune-related adverse event (transaminitis) occurred, which resolved with steroid therapy and a delay in therapy. PET2 was scored as Deauville 2 or 3 in six cases including three with large mediastinal masses, and as D 4 or 5 in 7 cases with residual activity (Figure 1). PET2 MTV and TLG could be calculated for 12 of 13 cases, (MTV: 42 - 774 cm2, median 134 cm2; TLG: 257 - 5924; median 814). All 12 patients who completed a subsequent scan (PET3) after 2 cycles of AVD are now in a metabolic CR (Deauville 1-3), including all 7 cases with residual activity after PET2.Conclusion: These interim data suggest that upfront PEM x's 3 is highly active in previously untreated cHL. PEM monotherapy resulted in complete metabolic responses in some patients including those with large mediastinal masses, and near complete responses, best represented by the decline in MTV and TLG compared with Deauville scores or Lugano criteria. Our preliminary data suggest that MTV and TLG are useful additional interim indicators of biologic activity when assessing response after PD-1 inhibitor therapy. [Display omitted] DisclosuresAllen:Merck: Research Funding; Bayer: Consultancy. Evens:Bayer: Consultancy; Janssen: Consultancy; Affimed: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Abbvie: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees. Pro:kiowa: Honoraria; Takeda Pharmaceuticals: Honoraria, Other: Travel expenses; portola: Honoraria; Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding. Advani:Millenium: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Agensys: Other: Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Kyowa: Other: Consulting/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Infinity: Other: Institutional Research Support. Winter:Merck: Honoraria, Research Funding.

Pembrolizumab for the Treatment of Disease Relapse Following Allogeneic Hematopoietic Cell Transplantation

Background: Disease relapse remains the primary cause of mortality following allogeneic hematopoietic cell transplantation (alloHCT). One important mechanism of disease relapse in this setting is failure of the graft-versus-tumor (GvT) effect, and the PD-1/PD-L1 axis may diminish GvT after alloSCT. We hypothesized that PD-1/PD-L1 interactions prevent donor-derived T cells from eliminating malignant cells expressing minor histocompatibility antigens, and that blocking PD-1/PD-L1 interactions with the anti-PD-1 antibody, pembrolizumab (pem), might restore GvT and induce clinical responses in patients (pts) with relapsed hematologic malignancies following alloHCT. However, PD-1 blockade therapy has been associated with severe graft-versus-host disease (GVHD) in murine models, and GVHD has been reported in humans treated with anti-PD-1 therapy after alloHCT. Thus, we developed a prospective clinical study to test the tolerability and preliminary efficacy of pembrolizumab in patients with relapsed leukemia/lymphoma after alloSCT.Methods: Pts with AML, MDS, or B cell lymphomas with biopsy-proven recurrence after alloSCT were eligible, as long as no active acute GVHD > grade 1 or chronic GVHD was present. Pts were treated with pem 200 mg IV q3 weeks for up to 2 years, provided that neither intolerable side-effects nor disease progression occurred. Pem could be delayed for treatment-limiting toxicities (TLT), defined as immune-related adverse events (irAEs) not meeting criteria for a dose-limiting toxicity (DLT). DLT was defined as the development of grade 3 or 4 acute GVHD/irAE, any unexpected grade > 2 toxicity related to pem, or development of > grade 2 vital organ dysfunction secondary to an irAE within 90 days of pem initiation. A two-stage mini-max design was chosen, with an early stopping rule for DLT after the first 11 patients were enrolled.Results: 11 pts (7 male, 4 female), mean age 49.5 yrs (range, 27-62 yrs) have been enrolled. 8 pts had AML and 3 had lymphoma (DLBCL - 2, cHL - 1). 6 pts had matched-related donors (MRD) and 5 pts had haploidentical/umbilical cord blood (haplo-cord) donors. Pts with MRD were conditioned with fludarabine, melphalan, and alemtuzumab, or fludarabine and busulfan. Pts with haplo-cord donors were conditioned with fludarabine, melphalan, and ATG. 5 pts had prior acute GVHD. Pts relapsed following alloHCT at a median of 453 days (range, 101-1021 days). A median of 2 cycles of pembrolizumab (range, 1-8) was administered. 3 pts are receiving ongoing treatment. 3 pts experienced a DLT due to an irAE (grade 3-4 pneumonitis 2 pts; grade 3 hyperthyroidism 1 pt), all of which occurred after 1-2 cycles of pem, and resolved after pem discontinuation and corticosteroid treatment. 1 pt experienced a TLT (grade 2 rash), but resumed pem treatment. Among all pts, irAEs of any grade occurred in 7 pts. 7 pts were evaluable for response. 3 pts (2 AML, 1 DLBCL) experienced progressive disease (PD), 2 pts (AML) had stable disease (SD), and 2 pts achieved CR (DLBCL, cHL). 1 pt with AML (myeloid sarcoma) in whom pem was discontinued for PD by PET/CT imaging had a concurrent tumor biopsy that revealed marked T cell infiltration and PD-L1 expression on a significant fraction of malignant myeloid cells, suggestive of possible inflammatory “pseudo-progression”. 1 pt in CR developed therapy-related AML unrelated to pem. Notably, both patients with CR following pem had PD-L1 gene-amplified lymphomas by FISH, and diffuse PD-L1 protein expression on pre-treatment biopsies. Currently, 4 pts have died, all due to disease progression, and 7 are alive. A total of 26 patients are expected to be enrolled.Conclusions: Treatment with pem in the post-alloHCT disease relapse setting is feasible, but can induce early and severe irAEs, requiring vigilant monitoring. To date, objective responses were seen in 2/3 lymphoma patients treated with pem. In AML, pem may be less effective, where a best response of SD was observed in 2 pts, and possible “pseudo-progression” in a patient with myeloid sarcoma. This study continues to accrue pts, and correlative analyses are underway. To our knowledge, these are the first prospective data of PD-1 blockade therapy in the post-alloHCT setting. DisclosuresKline:iTeos: Research Funding; Merck: Honoraria, Research Funding. Liu:BMS: Research Funding. Curran:Merck: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Bishop:Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment; Novartis Pharmaceuticals Corporation: Speakers Bureau.

A case report of pseudo-progression after pembrolizumab in metastatic gastric cancer and a review of immunotherapy in gastroesophageal tumors

In this report, we present the medical history of a 30-year-old male patient with HER2- and PD-L1-negative metastasized adenocarcinoma of the gastric cardia, who received three cycles of pembrolizumab (200 mg every 2 weeks) after the failure of the first-line (1L) treatment with docetaxel, cisplatin, 5‑fluorouracil (DCF). A restaging computed tomography (CT) scan for the chest and abdomen revealed an apparent progressive disease; therefore, the treatment was terminated. Five months after the termination of the treatment, a new CT scan demonstrated a spontaneous treatment response although no treatment was given during this time period, indicating pseudo-progression of the tumor in the first restaging after three cycles of pembrolizumab. This finding is apparently due to the long-term sustainable immunological effects of pembrolizumab. The current report will present this rare case in more detail and summarize the closed and ongoing clinical trials of immunotherapy drugs in gastroesophageal cancer.

Final Results of a Phase I Prospective Trial Evaluating the Combination of Stereotactic Body Radiation Therapy (SBRT) with Concurrent Pembrolizumab in Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC) or Melanoma

Synergy between immune checkpoint inhibition and radiation therapy enhances antitumoral immunity in preclinical models. We report the final results of the Phase I portion of a Phase I/II prospective trial designed to assess the safety and tolerability of SBRT delivered with concurrent pembrolizumab. Eligible patients had metastatic NSCLC or melanoma and ≥2 measurable sites of disease. Patients who had received prior anti-PD1 immunotherapy were eligible if their disease had progressed by RECIST criteria; these patients received SBRT at enrollment. Immunotherapy-naïve patients were treated with 200 mg of pembrolizumab q3 weeks until disease progression, then received SBRT. After SBRT, patients received pembrolizumab q3 weeks until coming off study for disease progression. Patients were assigned to an SBRT dose-escalation arm based on target location: either in the lung (arm A) or elsewhere (arm B). Twenty-four patients enrolled in the Phase I portion of the study (melanoma n=5; NSCLC n=19). 9 patients had received prior anti-PD-1 therapy and therefore got SBRT at enrollment. Fifteen patients were immunotherapy-naïve and received a mean of 8.3 cycles of pembrolizumab before disease progression and SBRT. The target SBRT dose of 30 Gy in 3 fractions was reached for each arm. No dose-limiting toxicities (DLTs) were observed within 60 days post-SBRT. Non-hematologic toxicities of grade 2 or higher occurring during the 60-day DLT window or during subsequent pembrolizumab treatment are presented in the table below, with immune-related adverse events noted. 5 of 24 patients (21%) had an immune mediated grade 2 or 3 adverse event during post-SBRT immunotherapy. Patients continued to receive pembrolizumab for a mean of 19.8 weeks post-SBRT (range: 0-52 weeks) before disease progression. We completed escalation to the planned dose of 30 Gy in 3 fractions for both arms without observing dose-limiting toxicity. Combination therapy was well tolerated. Preliminary efficacy data indicates that the addition of SBRT to a single site of disease resulted in a mean of 19.8 weeks of continued response. The phase II portion of the study continues enrollment; progress to date regarding efficacy as well as correlative studies of T cell responses in the peripheral blood will be presented.Abstract 34; TablePre SBRTArm A (Lung Target)Arm B (Non-Lung Target)30 Gy in 5 fx30 Gy in 3 fx30 Gy in 5 fx30 Gy in 3 fxn157647Gr 24 hypothyroid; n=1pneumonitis; n=122 colitis; n=103 pneumonitis; n=1Gr 31 hypothyroid; n=11 pneumonitis; n=12 enterocolitis; n=1pneumonitis; n=101 colitis; n=1Gr 400000Gr 500000 Open table in a new tab

A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours

BackgroundWe conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers.MethodsThere were two strata (12 patients each): (i) NSCLC/melanoma progressing on prior anti-PD-1 therapy, (ii) other cancer types; anti-PD-1-naive. Patients received 6 cycles of pembrolizumab, starting 1 week before HFRT. Patients had ≥2 lesions; only one was irradiated (8 Gy × 3 for first half; 17 Gy × 1 for second half in each stratum) and the other(s) followed for response.ResultsOf the 24 patients, 20 (83%) had treatment-related adverse events (AEs) (all grade 1 or 2). There were eight grade 3 AEs, none treatment related. There were no dose-limiting toxicities or grade 4/5 AEs. Stratum 1: two patients (of 12) with progression on prior PD-1 blockade experienced prolonged responses (9.2 and 28.1 months). Stratum 2: one patient experienced a complete response and two had prolonged stable disease (7.4 and 7.0 months). Immune profiling demonstrated that anti-PD-1 therapy and radiation induced a consistent increase in the proliferation marker Ki67 in PD-1-expressing CD8 T cells.ConclusionsHFRT was well tolerated with pembrolizumab, and in some patients with metastatic NSCLC or melanoma, it reinvigorated a systemic response despite previous progression on anti-PD-1 therapy. Clinical Trial Registration: NCT02303990 (www.clinicaltrials.gov).

A Rare Case of Hematochezia: Rectal Melanoma

Introduction. Anorectal melanoma is an aggressive, rare subtype of both anorectal masses and melanomas. We describe a case of rectal melanoma presenting with lower gastrointestinal (GI) symptoms. Clinical Summary. A 60 year old Caucasian male with a history of Hepatitis C (no cirrhosis, on Ledipasvir/sofosbuvir) presented with 3 weeks of progressively worsening abdominal pain, constipation, hematochezia, and narrow stool caliber. On exam, the patient was hemodynamically stable and without lymphadenopathy. Rectal exam was negative for anal fissures, external hemorrhoids, or gross blood, however, noted a palpable mass in the posterior rectal wall. A colonoscopy found 6 polyps (from <5-9mm) throughout the colon that were removed with snare polypectomy, and found to be tubular adenomas. Also, a 7.2cm rectal mass involving the dentate line was visualized. Histology was positive for melanoma, and immunohistochemistry was positive for S100 and melan-A. Rectal endoscopic ultrasound showed the mass abutt the muscularis propria without clear penetration into the serosa. A staging PET scan was unremarkable. In the next 8 months, the patient underwent 4 cycles of pembrolizumab and 2 cycles of ipilimumab with radiation therapy (XRT). Discussion. Rectal melanoma (RM) is a rare cancer representing 1% of anorectal malignancies, and less than 1% of melanomas. Most literature is case series or smaller reviews. Histologically, kit and S-100 mutations are common and BRAF mutations are rare; our patient was only S-100 positive. In some metastatic case studies, kit mutations direct imantinib therapy. First line treatment is wide local surgical resection, sometimes with XRT. The role of chemotherapy is unclear. Diagnosis is difficult as symptoms are nonspecific and lesions are difficult to detect on physical exam. Even when visualized, masses are often non-melanotic. Clinical suspicion is thus essential when evaluating a patient with lower GI symptoms. Unfortunately, anorectal melanoma has a poor prognosis. Median age at diagnosis is 69, median survival is 18 months, and most patients present with at least stage II disease. Wide local excision is safer than abdominoperineal resection but does not have a relative survival advantage. Our patient was not a surgical candidate and during chemotherapy had primary tumor growth and metastases to the lung, liver, and kidney. This case highlights a rare, aggressive GI malignancy and emphasizes maintaining a high clinical suspicion.1552_A Figure 1. melanotic mass area on colonoscopy1552_B Figure 2. rectal mass on endoscopic ultrasound

P2.13-22 Resistant Patterns to Osimertinib in Non-Small Cell Lung Cancer Patients with Both T790M and Sensitizing EGFR Mutation

Osimertinib is a 3rd generation, EGFR-TKI which is active for both sensitizing mutations and T790M of EGFR. Although it has proven its efficacy, the acquired resistance eventually occurs requiring the investigation for resistant mechanisms to provide overcoming strategies. We retrospectively reviewed the medical records of T790M+ lung cancer patients treated with osimertinib after acquiring resistance to 1st- or 2nd generation EGFR-TKI between February 2016 and June 2017 to evaluate the efficacy and safety of the drug. In addition, the moleculo-pathologic data of re-biopsy samples after the development of resistance to osimertinib were analyzed. In 23 patients included, the median age was 59.0 years and thirteen (56.5%) were female. The median duration of follow-up was 11.9 months. 17 patients achieved an objective response (73.9%) and the disease was controlled in 22 patients (95.7%). Median progression-free survival was 7.4 months (95% CI 3.6-11.0) and median overall survival was not reached. The adverse effects were minimal except one case of severe pneumonitis. Among 14 patients who finally experienced the disease progression during osimertinib, the re-biopsy was performed in 10 patients. T790M disappeared in 7 patients (70%) and one of them showed the wild-type conversion. Transformation to small cell carcinoma was observed in 2 patients who responded to chemotherapy with etoposide and cisplatin. A newly developed C797S mutation was detected in one patient. Interestingly, C797S disappeared after 6 cycles of pembrolizumab following osimertinib-resistance and the patient responded well to osimertinib again. Osimertinib showed the clinical activity and the favorable toxicity profile comparable to those of clinical trials in real world practice in Korea. The evaluation with repeated biopsy sample after osimertinib-resistance is needed to guide the following treatment strategy.

Sick sinus syndrome associated with anti-programmed cell death-1

BackgroundUse of anti-programmed cell death-1 (anti-PD-1) has been successful in treating many types of cancers. Despite its promising efficacy, immune-related adverse events are still a major concern. Immune-related cardiotoxicity, which is rare but fatal, has recently become a focus of attention. Cardiotoxicities including myocarditis, cardiomyopathy, cardiac fibrosis, heart block and cardiac arrest have been reported. Of these toxicities, myocarditis is often accompanied by dysrhythmia. The presentation of sick sinus syndrome as an immune-related adverse event has not yet been reported. Here, we reported the first case of sick sinus syndrome, a rare toxicity induced by anti-PD-1.Case presentationA 42-year-old male patient who had metastatic hepatocellular carcinoma failed treatment with sorafenib. Pembrolizumab at a fixed dose of 100 mg every three weeks was given. His heart rate gradually slowed down and he presented sick sinus syndrome with a lowest heart rate of 38 bpm after six cycles of pembrolizumab. He denied chest tightness, cold sweating, palpitation and dyspnea. Lab data including cardiac enzyme, electrolytes and thyroid function were all within a normal range. Simultaneously, he complained of fatigue, dizziness and anorexia with hypotension. Lab data revealed low cortisol and ACTH levels. Anti-PD-1 induced adrenal insufficiency was suspected. Low-dose cortisone (12.5 mg) was prescribed, and the patient’s symptoms, hypotension and sick sinus syndrome showed rapid improvement. Cortisone was gradually titrated and discontinued three weeks later. His sick sinus syndrome did not relapse and the cortisol and ACTH level returned to normal.ConclusionsSick sinus syndrome caused by anti-PD-1 treatment is a rare adverse event. With the development of sick sinus syndrome, myocarditis should be the first differential diagnosis because of its lethality. From this case, we learned that sick sinus syndrome may be a presentation of immune- or adrenal insufficiency-mediated sinus node dysfunction, both could be reversed with a glucocorticoid supplement.

Randomized Phase 1 Trial of Pembrolizumab with Neo-Adjuvant Versus Concomitant Stereotactic Body Radiotherapy in Metastatic Urothelial Carcinoma

Background: Preclinical data indicates that stereotactic body radiotherapy (SBRT) works synergistically with pembrolizumab, but the effect and potential toxicity might depend on the timing of SBRT. The current study assessed the safety of two different SBRT schedules in combination with pembrolizumab for metastatic urothelial carcinoma (mUC), and explored correlative biomarkers including circulating tumor DNA (ctDNA). Methods: An open-label phase 1 trial was conducted at Ghent University Hospital in patients with mUC to assess the dose-limiting toxicity (DLT) of the combination of pembrolizumab (200mg intravenously, 3-weekly) and SBRT (3x8Gy to the largest lesion). Patients were randomized (1:1) to receive SBRT either prior to the first (arm A) or the third (arm B) cycle of pembrolizumab. Blood was collected throughout the trial for biomarker analysis. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 4.0. Secondary endpoints included best overall response measured per Response Evaluation Criteria in Solid Tumors v1.1 (RECISTv1.1). Findings: Between November 14, 2016 and January 2, 2018, eighteen patients were randomized (nine to each arm) and started trial treatment. No DLT occurred. Treatment-related AEs grade 1-2 occurred in 6/9 and 9/9 patients in arm A and B respectively. One patient in arm B experienced lymphopenia grade 3, unrelated to SBRT. No treatment-related AEs grade 4- 5 occurred. An objective response rate as per RECISTv1.1 of 0% and 44·4% was noted in arm A and B respectively. Targeted sequencing of tissue DNA and ctDNA revealed high genomic concordance. A decline in ctDNA was observed in responding patients. Interpretation Neo-adjuvant and concomitant SBRT combined with pembrolizumab is safe, with potentially superior responses in the latter. ctDNA monitoring is feasible during disease evolution. Clinical Trial Number: The trial is registered on ClinicalTrials.gov (NCT02826564), and is complete. Funding Statement: This trial was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. Declaration of Interests: NS reports travel grants from Merck Sharpe & Dohme, Astellas, Bayer and Bristol-Myers Squibb. KD reports travel grants from Ipsen, Astellas, and Ferring; and honorarium from Ipsen, Astellas, Intuitive Surgical, and Medtronic Belgium. VF report travel grants and honorarium from Ipsen and Astellas. DDM reports a research grant from Roche; travel grants from Roche, Pfizer, and Astellas; and honorarium from Bristol-Myers Squibb, Pfizer, Janssen, and Bayer. LB reports a travel grant and honorarium from Incyte Biosciences. AWW reports honorarium from Sanofi and Janssen and research grants from Janssen. SR reports a research grant from Roche; travel grants from Merck Sharpe & Dohme, Roche, Pfizer, Bristol-Myers Squibb; and honorarium from Merck Sharpe & Dohme, Bristol-Myers Squibb, Roche, and Pfizer. PO reports research grants from Merck Sharpe & Dohme, Astellas and Janssen; travel grants from Ipsen and Ferring Pharmaceuticals; and honorarium from Ferring and Bayer. All other authors declare no competing interests. Merck Sharpe & Dohme provided financial support and pembrolizumab for the present study. Ethics Approval Statement: The study protocol was approved by the Ethics Committee of Ghent University Hospital (EC2016/0661).

2568 Pembrolizumab for patients with leptomeningeal disease from advanced solid tumors

OBJECTIVES/SPECIFIC AIMS: Pembrolizumab is an anti-PD-1 immune checkpoint antibody that has demonstrated promising anti-tumor activity in patients with solid tumor malignancies, including patients with brain metastases from malignant melanoma and non-small cell lung cancer. Leptomeningeal disease (LMD) is a rare form of malignant spread to the central nervous system (CNS), that occurs in 2%–10% of patients with solid tumors, most commonly in breast cancer and non-small cell lung cancer. We propose an open-label phase II study of pembrolizumab in patients with LMD from advanced solid tumors (NCT03091478). This study aims to determine if pembrolizumab therapy can lead to a radiologic, cytologic or clinical response in the CNS, in patients with LMD. METHODS/STUDY POPULATION: Patients with pathologically confirmed advanced solid tumors, and either radiologic or cytologic evidence of LMD, will be identified at a single institution. Radiologic LMD will be defined as a &gt;4 mm area of measurable LMD on gadolinium-enhanced MRI brain/total-spine; and cytologic LMD will be defined as the presence of malignant cells on CSF cytology. Patients will be excluded if they have: active autoimmune conditions that require immunosuppression, received radiation therapy to the only area of measurable LMD within 3 months of study enrollment, have an ECOG performance status &lt;1. Once enrolled, patients will receive pembrolizumab 200 mg intravenously every 3-weeks, until disease progression or unacceptable toxicity. Patients will have CSF sample sampling, blood draws, radiologic imaging of the body (CT), brain/total-spine (gadolinium-enhanced MRI) pre-treatment, after 2 and after 4 cycles of therapy, for response assessment and correlative studies. The primary endpoint of the study is CNS response assessed at 12 weeks/after 4 cycles of pembrolizumab, defined either as radiologic response (reduction in size of LMD on gadolinium-enhanced MRI) and/or cytologic response (conversion of positive to negative CSF cytology on 2 consecutive samples) and/or clinical response. Secondary endpoints will include progression-free survival, overall survival, and safety. To explore the mechanisms by which pembrolizumab may affect LMD, we will assess dynamic changes in genomic and immunologic markers in the CSF and serum pre and post pembrolizumab using next-generation sequencing and multi-color flow cytometry, respectively. RESULTS/ANTICIPATED RESULTS: We will aim to accrue a total of 20 patients, allowing for a 10% drop-out rate, the final sample size will include 18 patients who have received at least 1 dose of pembrolizumab. CNS-response at 12 weeks will be assessed radiologically +/− cytologically, and the proportion of patients with CNS response and associated 95% confidence interval with be reported. CNS-progression-free survival and overall survival will be assessed using the Kaplan-Meier method. Cause of death will be recorded. Safety will be assessed as detailed above, and monitored as per an institutional Data Safety and Monitoring Plan. Exploratory endpoints will include genomic testing of tumor cells and cell-free DNA in CSF and serum, and immunologic studies of immune cells in CSF and serum at pre-defined timepoints. These data will be presented descriptively. We conservatively estimate that we will accrue 1 patient per month at our institution. Study duration will be approximately 24 months, allowing 18 months for accrual and 6 months for follow-up and data analysis. DISCUSSION/SIGNIFICANCE OF IMPACT: There are no currently FDA-approved therapies for patients with LMD from solid tumors. Anti-PD-1 immunotherapy is a promising class of agents, with known efficacy in patients with CNS metastatic disease, across tumor types. This study seeks to identify whether pembrolizumab may lead to CNS responses in patients with LMD. Additionally, genomic and immunologic analyses in CSF and blood pre and post-pembrolizumab may identify mechanisms by which immunotherapy affects the CNS in patients with LMD.

Safety and clinical activity of pembrolizumab immunotherapy and multi-organ site ablative stereotactic body radiotherapy (iMOSART) in patients with advanced solid tumors.

20 Background: Clinical responses to PD1 blockade have been linked to IFN-γ associated gene expression in the tumor microenvironment. Stereotactic body radiotherapy (SBRT) can stimulate innate and adaptive immunity to potentially augment immunotherapy. Anti-PD1 treatment outcomes are improved with lower disease burden and multi-site radiation is an emerging paradigm for eradicating metastatic disease. Methods: We conducted a phase I study for patients with metastatic solid tumors who progressed on standard treatment. The primary aim was to evaluate the safety of pembrolizumab Immunotherapy with Multi-Organ Site Ablative stereotactic body Radiation Therapy (iMOSART). Two to four metastases were chosen for each patient and not all sites of disease were targeted with SBRT. Metastases &gt; 65cc were partially irradiated. Pembrolizumab was initiated within 7 days after the final SBRT treatment. Results: 79 patients were enrolled, three patients did not receive any treatment and three patients only received SBRT. The 73 patients included in the analysis were treated with SBRT and at least 1 cycle of pembrolizumab. 94.5% of patients had two lesions treated with SBRT. Median follow-up for toxicity was 5.5 months (IQR 3.3-8.1). Six patients experienced dose-limiting toxicity (DLT) with no radiation dose reductions. RECIST overall objective response rate was 13.5% in the 68 patients with imaging follow-up. Superior control of irradiated lesions was observed compared to non-irradiated target lesions for the 52 patients with paired data (p = 0·0005) with a mean percent tumor burden change -21·7% (SD 24·3%) for irradiated lesions vs. 1·7% (SD 46·3%) for non-irradiated lesions (p = 0·0008). While abscopal response defined by 30% reduction in any single non-irradiated measurable lesion was present in 26·9% of patients, abscopal response was 13·2% when defined by 30% reduction in aggregate diameter of non-irradiated measurable lesions. Conclusions: iMOSART was well tolerated with acceptable toxicity. Further randomized studies are warranted to investigate the potential clinical benefit of this combination approach. Clinical trial information: NCT02608385.

Pembrolizumab for recurrent/metastatic head and neck squamous cell carcinoma in an Asian population.

Head and neck squamous cell carcinoma (HNSCC) has a high prevalence and is a major cause of cancer deaths in Taiwan. However, there is still no effective salvage therapy that prolongs the life expectancy of patients with recurrent/metastatic (R/M) HNSCC. Immune checkpoint therapy that targets the programmed cell death protein 1 (PD-1) may provide clinical benefit for these patients. We analyzed 22 R/M HNSCC patients who received pembrolizumab, a monoclonal antibody against PD-1, as salvage therapy. Intravenous pembrolizumab was given at a fixed dosage of 100 or 200 mg every 3 weeks. Three patients also received local palliative radiotherapy, but no patients received chemotherapy or targeted drugs. Seventeen patients (77.3%) received at least 3 cycles of pembrolizumab. Based on Response Evaluation Criteria in Solid Tumors criteria (ver. 1.1), 2 patients (9.1%) had complete response, 5 (22.7%) had partial response, and 6 (27.3%) had stable disease, corresponding to a disease control rate of 59.1%. Four patients had confirmed disease progression, 2 of whom had continuous progression over the target lesion after shrinkage of other metastases. One patient developed immune-related pneumonitis that resolved quickly after steroid treatment. Another patient developed itchy skin rashes immediately after administration of pembrolizumab, and this was controlled by an antihistamine. There were no other severe adverse effects. Pembrolizumab is beneficial and well-tolerated for some patients with refractory R/M HNSCC. However, it is important to identify biomarkers to identify the most responsive patients when designing future trials.

Immune-related pneumonitis caused by programmed death-1 inhibitor Pembrolizumab: a case report and literature review

Objective: To investigate the risk factors, clinical manifestations, radiological features, diagnosis, treatment and prognosis of immune-related pneumonitis caused by programmed death-1(PD-1)/PD-L1 inhibitors. Methods: The clinical data of immune-related pneumonitis caused by PD-1 inhibitor Pembrolizumab in a patient with advanced esophageal carcinoma admitted to the 307(th) Hospital of Chinese People's Liberation Army was retrospectively analyzed and the related literatures were reviewed. We searched Medline database using the keywords"PD-1 inhibitor","PD-L1 inhibitor","Pembrolizumab","Nivolumab","Atezolizumab"combined with"Pneumonitis"by Mar 31, 2017. Results: The patient was a 60-year-old male presented with progression disease after surgery, local radiation and couples of chemotherapy for his esophageal carcinoma. Then pembrolizumab, a kind of PD-l inhibitors, was given intravenously every 3 weeks with the average dosage 3 mg per kg. After six cycles of pembrolizumab, the patient began to have fever, cough and dyspnea, which aggravated gradually. Chest CT showed diffuse ground glass opacity, exudation and consolidation in both lungs and little pleural effusion in the right side. Cellular interstitial pneumonitis was confirmed by pathological examination. The patient's symptoms were alleviated after enough steroids and chest CT showed pulmonary infiltration was also absorbed. But the pneumonitis reoccurred twice after stopping or tapering steroids quickly and could also be controlled by using steroids again. Now the patient was still given steroids treatment and the primary esophageal cancer remained stable. 14 articles were retrieved and 88 cases of immune-related pneumonitis caused by PD-1/PD-L1 inhibitors were reported. Among these 89 cases with immune-related pneumonitis, both male and female could attack and the median age was 67 years old. Most cases were grade 1 or 2. The common clinical manifestations were dyspnea, cough, fever and other immune-related damages. And about 20% patients had no symptoms. Ground glass opacities, reticular opacities, consolidation and centrilobular nodules were the common radiological features. The commonest histologic pattern of pneumonitis associated with anti-PD-1/PD-L1 therapy on lung biopsy was organizing pneumonia. Adequate steroid and tapering slowly is the standard treatment. Immunosuppressive agents could be added in some serious cases. The prognosis was relatively good. Most patients were alleviated but few patients died of progression disease or infections during treatment. Conclusions: Immune-related pneumonitis associated with PD-l/PD-L1 inhibitor should be aware of; early detection, early treatment, and the prognosis could be better.

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).

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial

Preclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab. We assessed patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial at a single institution (University of California, Los Angeles, CA, USA). Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 1 or less, had adequate organ function, and no history of pneumonitis. Patients received pembrolizumab at a dose of either 2 mg/kg of bodyweight or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, until disease progression, unacceptable toxicity, or other protocol-defined reasons for discontinuation. Disease response and pulmonary toxicity were prospectively assessed by Immune-related Response Criteria and Common Terminology Criteria for Adverse Events version 4.0. The primary objective of the KEYNOTE-001 trial was to assess the safety, side-effect profile, and antitumour activity of pembrolizumab. For our secondary analysis, patients were divided into subgroups to compare patients who previously received radiotherapy with patients who had not. Our primary objective was to determine whether previous radiotherapy affected progression-free survival, overall survival, and pulmonary toxicity in the intention-to-treat population. The KEYNOTE-001 trial was registered with ClinicalTrials.gov, number NCT01295827. Between May 22, 2012, and July 11, 2014, 98 patients were enrolled and received their first cycle of pembrolizumab. One patient was lost to follow-up. 42 (43%) of 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first cycle of pembrolizumab. 38 (39%) of 97 patients received extracranial radiotherapy and 24 (25%) of 97 patients received thoracic radiotherapy. Median follow-up for surviving patients was 32·5 months (IQR 29·8-34·1). Progression-free survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (hazard ratio [HR] 0·56 [95% CI 0·34-0·91], p=0·019; median progression-free survival 4·4 months [95% CI 2·1-8·6] vs 2·1 months [1·6-2·3]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (HR 0·50 [0·30-0·84], p=0·0084; median progression-free survival 6·3 months [95% CI 2·1-10·4] vs 2·0 months [1·8-2·1]). Overall survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (HR 0·58 [95% CI 0·36-0·94], p=0·026; median overall survival 10·7 months [95% CI 6·5-18·9] vs 5·3 months [2·7-7·7]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (0·59 [95% CI 0·36-0·96], p=0·034; median overall survival 11·6 months [95% CI 6·5-20·5] vs 5·3 months [3·0-8·5]). 15 (63%) of 24 patients who had previously received thoracic radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy. Three (13%) patients with previous thoracic radiotherapy had treatment-related pulmonary toxicity compared with one (1%) of those without; frequency of grade 3 or worse treatment-related pulmonary toxicities was similar (one patient in each group). Our data suggest that previous treatment with radiotherapy in patients with advanced NSCLC results in longer progression-free survival and overall survival with pembrolizumab treatment than that seen in patients who did not have previous radiotherapy, with an acceptable safety profile. Further clinical trials investigating this combination are needed to determine the optimal treatment strategy for patients with advanced NSCLC. US National Institutes of Health.

Short course pembrolizumab in complete responders with advanced non-small cell lung cancer.

e20537 Background: Pembrolizumab has been available in Singapore since October 2014 for clinical use. All clinical trial protocols of Pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) require a 2 year period of treatment in responders, even in complete responders. It is not known if shorter treatment durations in complete responders can afford reasonable progression free interval (PFS). Such abbreviated treatment in complete responders would result in significant cost savings and lesser side effects. Methods: A single physician practising at a single private medical oncology center in Singapore collated consecutive cases of advanced NSCLC seen by him and treated with Pembrolizumab from October 2014 till December 2016. All were smokers except for 2 patients. All patients were biopsy and imaging proven to have advanced NSCLC. 46 patients were treated with Pembrolizumab 2mg/kg body weight 3 weekly and observed with sequential imaging every 3-6 months with the first assessment scan after Cycle 4. All complete responders by imaging stopped treatment after 4 cycles of Pembrolizumab by mutual consent. PD-L1 IHC testing by DAKO 22C3 was not done on any of the patients’ tumours as the test has only been available in Singapore since December 2016. Results: Cut-off date for analysis of data was 1 Feb 2017. 4 out of 46 patients (9%) achieved a complete metabolic response on FDG PET by irRC and/or CT scans by RECIST 1.1. All 4 patients with complete response (CR) (except Patient #3) were smokers. All 4 patients remain in CR with ECOG Performance Status (PS) 0 without any further treatment. Conclusions: Real world clinical usage of Pembrolizumab in advanced NSCLC can afford long PFS in complete responders in spite of abbreviated treatment of 4 cycles. Clinical trials should be designed to address this issue due to its impact on health care costs. [Table: see text]