Addition Of Pembrolizumab Research Articles

Characterization of a patient-specific T-cell and tumor cell coculture model of immuno-cytotoxicity in colorectal cancer.

e14178 Background: Colorectal Cancer (CRC) is the third most commonly diagnosed cancer in the world. Yet, CRC has been difficult to treat with immunotherapy, as majority (85%) of CRC are Microsatellite stable (MSS), lowly immunogenic and do not respond well. To investigate immuno-cytotoxicity in MSS cancers, we set up an ex vivo co-culture model using patient-derived tumor epithelial cells and autologous tumor-infiltrating lymphocytes (TILs). Aims: To perform phenotypic and functional characterisation of the model, and show we are able to modulate immuno-cytotoxicity. Methods: Fresh tumor, adjacent normal and/or liver metastasis samples were collected and freshly dissociated from 29 colorectal cancer patients undergoing surgery. TILs and tumor epithelial cells were grown in culture. Weekly immunophenotyping of TILs was performed via flow cytometry and data was analysed to identify temporal changes in proportions of cell types. To modulate cytotoxicity, epithelial cell lines were co-cultured with autologous and allogeneic TILs at various effector:target ratios with and without anti-PD1 (Pembrolizumab). Caspase dye was used to detect apoptosis and measure cell death. Results: TILs from most patients were successfully expanded, with a theoretical potential of up to 10,000 times. CD4+ T cells were selectively expanded, while CD8+ T cells decreased in proportion over time. A select group of patients showed an opposite trend. Cell type proportions in metastases mirrored those of the primary tumour while NK cells expanded more in tumour samples than normal samples. Selection proceeded up to 3 weeks then decreased. In the cytotoxicity experiment, we show that cell death is increased at higher effector:target ratios in the presence of autologous TILs. Addition of Pembrolizumab further modulates cytotoxicity in vitro. Conclusions: We have developed and characterised an autologous T cell and epithelial cell co-culture system to evaluate immuno-cytotoxicity in colorectal cancer. This will allow screening of perturbations for improved immuno-cytotoxicity in colorectal cancer.

A phase I/II study of blinatumomab in combination with pembrolizumab for adults with relapsed refractory B-lineage acute lymphoblastic leukemia: University of California Hematologic Malignancies Consortium Study 1504.

TPS7064 Background: Outcomes for adults with relapsed/refractory B-cell ALL (R/R B-ALL) remain poor despite new targeted therapies. Blinatumomab is an anti-CD19/CD3 bifunctional T-cell engaging antibody that was superior to conventional salvage therapy for remission and overall survival in a Phase III study of patients with R/R B-ALL. The CR/CRh rate for blinatumomab was 65.5% with < 50% marrow lymphoblasts but dropped to 34.4% with ≥ 50% marrow lymphoblasts. Clinical and pre-clinical findings suggest that PD-L1 overexpression on lymphoblasts and in the bone marrow may mediate resistance to blinatumomab by inhibiting T-cell activation. We hypothesize that addition of pembrolizumab will improve CR/CRh rates to blinatumomab in R/R B-cell ALL. Methods: We are conducting a phase I/II multicenter trial to evaluate the safety and efficacy of blinatumomab with pembrolizumab in adults with R/R B-ALL and a high bone marrow lymphoblast percentage (NCT 03160079). The primary endpoint is ORR (CR+CRh) after 1-2 cycles with secondary endpoints of AEs, MRD-negative CR/CRh rate, 2-year DFS, 2-year OS, and allogeneic HCT rate. Exploratory studies are evaluating cytokine expression, PD-1 expression on T-cells, PD-L1 and PD-L2 protein expression on lymphoblasts, and T-cell populations at diagnosis and in response to therapy. Eligibility includes: adults with R/R CD19+ B-ALL after ≥ 1 prior line of therapy, R/R Ph+ B-ALL must fail a 2nd- or 3rd-generation TKI or be TKI intolerant, > 50% lymphoblasts on screening bone marrow sample. Blinatumomab is given by continuous IV at 9 mcg/day days 1-7 of cycle 1, 28 mcg/day days 8-28 of cycle 1, then at 28 mcg/day days 1-28 in subsequent cycles. Pembrolizumab 200 mg IV is given on days 15 and 36 of each 42-day cycle. Patients in CR/CRh after 1-2 cycles will complete 5 cycles. Patients not in CR/CRh after 2 cycles of therapy or progressing after Day 15 of cycle 1 go off study. CNS prophylaxis with IT methotrexate is given at screening and once per cycle. A phase I run-in of 3-6 patients precedes accrual of 18-21 patients for a target of 24. The study opened in July 2017 and 4 patients have been treated. No DLTs have occurred to date. Clinical trial information: NCT03160079.

Incidence and patterns of immune related adverse events (irAEs) during chemoimmunotherapy (ChemoIO) in patients with advanced nonsquamous NSCLC.

e20705 Background: Based on superior outcomes noted in KEYNOTE-189 with the addition of pembrolizumab to platinum doublet chemotherapy, a majority of pts with nonsquamous NSCLC are now treated with chemoIO. irAEs can cause significant morbidity and occasionally mortality in pts treated with immunotherapy. Since chemotherapy is immunosuppressive, it is plausible that incidence of irAEs would be lower in pts receiving chemoIO compared to immunotherapy. The incidence of irAEs in KEYNOTE-189 was 22.7% vs 29.2% in KEYNOTE-024 with pembrolizumab monotherapy. We sought to evaluate the incidence and patterns of irAEs in pts with advanced nonsquamous NSCLC treated with chemoIO at our institution and to determine if the rate varied with the intensity of chemotherapy [carboplatin/ pemetrexed/ pembrolizumab (CPP) vs pemetrexed/ pembrolizumab (PP)]. Methods: We retrospectively reviewed the charts of 73 pts with advanced nonsquamous NSCLC who received CPP followed by maintenance PP. In addition to clinicopathologic variables, we noted the date, incidence, type and grade of irAEs. Descriptive statistics were used to report the incidence and patterns of irAEs. McNemar’s test was used to determine if there was a significant difference in rate of irAEs during CPP vs PP. Results: Of the 73 pts, 52% were females, 67% former smokers, 49% had previously received radiation and 11% had a history of autoimmune disease. 35 pts received 4 cycles of CPP. 21 patients (28%) developed irAEs, of which 6 had irAEs during CPP and 15 developed irAEs on PP. The rate of irAEs was significantly higher after stopping carboplatin (p = 0.049). 10 pts (13%) stopped pembrolizumab due to irAEs. Organ systems involved and grade of irAEs are listed below. Conclusions: The immunosuppressive effects of intensive chemotherapy may be protective against irAEs in pts receiving chemoIO. [Table: see text]

Abstract OT3-04-02: Neoadjuvant Her2-targeted therapy +/- immunotherapy with pembrolizumab (neoHIP): An open label randomized phase II trial

Abstract Background: In preclinical models HER2-directed therapy administered with checkpoint blockade is synergistic. Clinically, trastuzumab administered with pembrolizumab-mediated checkpoint blockade in trastuzumab-resistant HER2-positive metastatic breast cancer was safe and demonstrated modest activity. However, because checkpoint blockade can confer improved responses when administered earlier in the course of disease, trastuzumab with pembrolizumab administered in the curative-intent, treatment-naive setting may confer life-long, tumor-specific immunity and ultimately, improve cure rates. Moreover, the potential synergy of trastuzumab and pembrolizumab with paclitaxel may overcome the need for dual HER2-blockade. The neo-HIP study is a randomized, multicenter, phase II, open-label trial to evaluate the efficacy and safety of weekly paclitaxel, trastuzumab plus pertuzumab (THP) vs weekly THP plus pembrolizumab (THP-K) vs a HER2 monotherapy regimen (TH-K) as neoadjuvant treatment in patients with HER2-positive early stage invasive breast cancer. Methods:Patients ≥18 years old with previously untreated, non-metastatic, stage II-III, HER2-positive (by ASCO/CAP guidelines) breast cancer are eligible. Patients with inflammatory breast cancer or bilateral primary tumors are excluded. Adequate organ function and ECOG PS 0-1 are required. Approximately 174 patients will be randomly assigned to 1 of 3 arms with stratification by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, patients will receive T at 80mg/m2 weekly for 12 weeks, H at 8mg/Kg (1 loading dose) and then 6mg/Kg IV every 3 weeks x 3 doses, P at 840mg (1 loading dose) and then 420mg/Kg IV every 3 weeks x 3 doses (THP). In arm B, patients will receive the same regimen as arm A with the addition of pembrolizumab 200mg IV every 3 weeks x 4 doses (THP-K). In arm C, patients will receive the same regimen as arm B, but without pertuzumab (TH-K). Definitive surgery will be 3-6 weeks after the last treatment dose. After surgery, patients in all arms willbe treated per the treating physician's discretion. After completion of post-operative chemotherapy, patients will receive radiotherapy per local clinical standard and those patients whose tumors are hormone-receptor positive will receive hormone therapy as per local standard-of-care. The purpose of this phase II study is to identify whether Arm B (THP-K) and/or Arm C (TH-K) demonstrate a clinically significant improvement in pCR rate when compared with Arm A (THP). The primary end point is pCR rate in the breast and axilla (ypT0/Tis ypN0). Secondary end points include pCR rate by ypT0ypN0 and ypT0/Tis, residual cancer burden index, event free survival, breast conserving surgery rate, safety and overall survival. Exploratory correlative studies will characterize the immunologic responses to the interventions and explore potential predictors of efficacy and toxicity. Citation Format: McArthur HL, Leal JHS, DiLauro Abaya C, Basho R, Coleman H, Shiao S, Knott S, Tighiouart M, Dadmanesh F, Giuliano A, Verma S. Neoadjuvant Her2-targeted therapy +/- immunotherapy with pembrolizumab (neoHIP): An open label randomized phase II trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-04-02.

Cost-effectiveness of pembrolizumab in combination with chemotherapy versus chemotherapy and pembrolizumab monotherapy in the first-line treatment of squamous non-small-cell lung cancer in the US

Objective: To describe the cost-effectiveness of pembrolizumab plus chemotherapy (carboplatin and paclitaxel or nab-paclitaxel; P + C) in metastatic, squamous, non-small-cell lung cancer (NSCLC) patients in the US.Methods: A model comparing P + C versus C alone is developed utilizing partitioned survival analysis. Primary clinical efficacy, treatment utilization, health utility and safety data are derived from the KEYNOTE-407 trial and projected over 20 years. Costs for drugs and non-drug disease management are also incorporated. Additionally, the cost-effectiveness of P + C vs. pembrolizumab monotherapy (P) is evaluated via an indirect treatment comparison, for patient subgroups with PD-L1 Tumor Proportion Score (TPS) ≥ 50% and 1–49%.Results: Overall, P + C is projected to increase life expectancy by 1.95 years vs. C (3.86 versus 1.91). The resultant ICER is $86,293/QALY. In patients with PD-L1 ≥ 50%, 1–49% and <1 the corresponding incremental cost-effectiveness ratios (ICERs) are $99,777/QALY, $85,986/QALY and $87,507/QALY, respectively. Versus P, in the PD-L1 ≥ 50% subgroup, P + C appears cost saving; however, this result should be interpreted with caution as there is considerable uncertainty in the relative efficacy of these comparators.Conclusions: Across all eligible patients, the addition of pembrolizumab to chemotherapy is projected to approximately double life expectancy, yielding an extension to a point not previously seen in metastatic squamous NSCLC. Overall, and within all relevant PD-L1 subgroups, use of P + C yields an ICER below $100,000/QALY, and can be a cost-effective first-line treatment for eligible metastatic squamous NSCLC patients for whom chemotherapy is currently administered. In the PD-L1 ≥ 50% subgroup, additional follow-up within trials of pembrolizumab plus chemotherapy and pembrolizumab monotherapy are needed to better define cost-effectiveness between these comparators.

IMMUNOTHERAPY FOR NSCLC: THE RIGHT TREATMENT FOR THE RIGHT PERSON

Lung cancer is the leading cause of mortality from malignant tumors all over the world. Since most patients at the time of diagnosis already have stage III-IV of the disease, the search for new effective treatment strategies for advanced NSCLC is the most important problem of modern oncology. The results of the study of the anti-PD1 monoclonal antibody pembrolizumab were a real breakthrough in the treatment of NSCLC. In the KEYN0TE-001 study, the expression of PD-L1 on tumor cells was validated as a predictive biomarker of the drug's efficiency. Pembrolizumab demonstrated the possibility of achieving long-term objective responses, and a 4-year 0S with all histological types in the subgroup of pre-treated patients with PD-L1 expression&gt; 50% was 24.8% and 15.6% in the PD-L1&gt; 1% group. In a phase 2/3 randomized study KEYN0TE-10 in the 2nd line treatment of NSCLC with PD-L1 expression &gt; 1% pembrolizumab significantly increased life expectancy compared to docetaxel and confirmed the possibility of longterm duration of objective responses, even after cessation of treatment. Then the focus of research shifted to the 1st line of treatment. About 30% of patients with NSCLC have a high level of PD-L1 expression on tumor cells and demonstrate the most impressive response to pembrolizumab therapy. A randomized phase 3 study KEYN0TE-024 compared the effectiveness of pembrolizumab monotherapy with a standard platinum combination in patients with advanced NSCLC with a high level of PD-L1 expression without EGFR mutations or ALK translocation. Compared with the platinum doublet the administration of pembrolizumab significantly increased all estimated parameters, including the median of progression-free survival (mPFS was 10.3 months versus 6 months; HR = 0.50; 95% CI 0.37-0.68, p &lt; 0.001), the objective response rate (ORR 44.8% versus 27.8%), duration of response (in the pembrolizumab arm the median was not reached, in the chemotherapy (CT) group - 6.3 months). Despite the approved crossover, the use of pembrolizumab in the 1st line of treatment more than doubled the life expectancy of NSCLC patients with high PD-L1 expression as compared to CT: the median overall survival (OS) was 30.0 months versus 14.2 months (HR = 0.63, p = 0.002), 1-year OS 70.3% versus 54.8%; 2-year OS - 51.5% versus 34.5%. The remaining population to study were untreated patients with any level of PD-L1 expression. A randomized phase 3 study KEYNOTE-189 evaluated the effectiveness of adding pembrolizumab to the platinum combination in the 1st line treatment of non-squamous NSCLC without EGFR and ALK mutations with any PD-L1 expression. The addition of pembrolizumab to the standard 1st line CT significantly increased all estimated efficacy indicators including OS, PFS and ORR. After a median follow-up of 10.5 months the median OS in the pembrolizumab combination group was not reached and in CT group was 11.3 months. The estimated 12-months survival was 69.2% and 49.4% respectively (HR = 0.49; 95% CI 0.38-0,64; p &lt;0.001). The median PFS was 8.8 months versus 4.9 months, alive 1 year without progression 34.1% and 17.3% of patients respectively (HR = 0.52; p &lt;0.001). The ORR in the group with pembrolizumab reached 47.6% versus 18.9% in CT group, moreover the tumor regressions were much longer. Finally a randomized 3-phase study KEYN0TE-407 evaluated the effectiveness of adding pembrolizumab to 1st-line CT of NSCLC with squamous histology with any PD-L1 expression. As the first analysis showed, the addition of permboli-zumab significantly increased OS of patients with squamous NSCLC, median OS 15.9 months versus 11.3 months in the groups of pembrolizumab + CT and placebo + CT respectively (HR = 0.64; 95% CI 0,49-0.95; p = 0.0006), median PFS 6.4 months and 4.8 months respectively (HR = 0.56; 95% CI 0.450.70; p &lt;0, 0001) and OrR 57.9% versus 38.4%, the median response duration 7.7 months versus 4.8 months. Thus, the convincing advantages of using pembrolizumab in 1st line therapy were demonstrated in 3 randomized phase 3 studies: in monotherapy of NSCLC of any histological subtype with high PD-L1 expression, and in combination with CT in squamous and non-squamous hystologies regardless of the level of PD-L1 expression.

Pembrolizumab Enhances the Anti-Leukemia Activity of Antigen Specific Cytotoxic T Lymphocytes

▪Many aggressive hematologic malignancies are exquisitely responsive to immunotherapy. While allogeneic (allo) hematopoietic stem cell transplantation (SCT) is the prime example of anti-leukemia immunotherapy, it is highly toxic, limiting its application to patients with aggressive disease and a good performance status. Although targeting leukemia-associated antigens (LAA) with antigen specific cytotoxic T lymphocytes (CTL) and chimeric antigen receptor (CAR) T cells has proven to be a successful immunotherapeutic option, the immune response generated with these approaches often fails to fully eradicate the underlying malignancy. The expression of immune inhibitory molecules and their ligands by myeloid leukemia cells and leukemia-specific T cells could contribute to the failure of cellular immunotherapy approaches for acute myeloid leukemia (AML). Specifically, blocking the PD1/PD-L1 pathway using antibodies was shown to enhance the graft versus leukemia response in murine leukemia transplant models, and promising results with immune checkpoint blockade have been demonstrated in clinical trials for patients with AML. We therefore investigated the role of blocking the PD1/PD-L1 pathway in combination with adoptive cellular immunotherapy in the setting of AML. We used pembrolizumab in combination with CTLs that target the HLA-A2 restricted myeloid leukemia antigens CG1, derived from cathepsin G, and PR1, derived from neutrophil elastase and proteinase 3.Using a standard calcein AM in vitro cytotoxicity assay, we co-cultured AML targets, including U937 HLA-A2+ (U937-A2) AML cell line and primary patient AML, with CG1-CTL and PR1-CTL. AML cells were loaded with calcein AM and then incubated with CTL at increasing effector to target ratios. Pembrolizumab or isotype antibody was added to the cultures. After 4 hours, calcein AM was measured to determine cell viability. Our results demonstrated that U937-A2 cells and patient primary AML samples can be effectively lysed by CG1/PR1 CTL. In vitro lysis of AML by CTL was enhanced after the addition of pembrolizumab in comparison with the AML cells that were co-cultured only with CTL. Killing was dose-dependent and decreased at the lower effector:target ratios. We then tested whether anti-leukemia activity can be enhanced in vivo. For these experiments, NOD/SCID gamma (NSG) mice were engrafted with U937-A2 cells or patient AML intravenously (IV) via tail vein at a dose of 1 x 106 to 1 x 107 cells. After confirming engraftment (1-5% PB HLA-A2+/human (h) CD45+ cells), CG1-CTL and PR1-CTL (0.5 x 106) were administered to mice IV via tail vein and pembrolizumab or isotype antibody [100ug/mouse] was given intraperitoneally 4 times over 2 weeks. Mice were monitored for clinical graft versus host disease (GVHD) and AML 3 times/week. Mice were sacrificed at approximately 2 weeks following treatment and bone marrow (BM) was processed and analyzed for residual AML (Human[h] CD45+/mouse[m] CD45- cells) by flow cytometry. Our data demonstrate a decrease in U937-A2 (Figure) and primary AML after treatment with CG1/PR1-CTL. This decrease was enhanced when pembrolizumab was administered to the CTL-treated mice in comparison with mice treated with pembrolizumab only, CTL only, or CTL+ isotype. Furthermore, there was no increased toxicity or GVHD after the addition of pembrolizumab. Together these data highlight the potential for combination immune checkpoint blockade and antigen specific CTL to eradicate AML in vitro and in vivo. [Display omitted] DisclosuresDaver:Incyte: Consultancy; BMS: Research Funding; ImmunoGen: Consultancy; ARIAD: Research Funding; Sunesis: Consultancy; Alexion: Consultancy; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Research Funding; Incyte: Research Funding; Karyopharm: Research Funding; Otsuka: Consultancy; Novartis: Consultancy; Kiromic: Research Funding; Karyopharm: Consultancy; Pfizer: Consultancy; Pfizer: Research Funding.

Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia

AbstractCAR T cell therapy in relapsed B-ALL can result in complete response (CR) rates of 80-90%, but relapse-free survival declines to 60% within the first 12-months due to both CD19-positive and negative relapses. CD19-positive relapses that occur during this time are largely due to early CAR T cell loss. We hypothesize that inhibiting the PD-1:PD-L1 (programmed cell death 1) checkpoint axis may decrease T cell exhaustion, thereby improving CAR T cell function and persistence. We report our single institution experience of the use of PD-1 inhibitors in patients with relapsed or refractory B lymphoblastic malignancies treated with CD19-directed CAR T cell therapy.Methods: Patients treated with CD19-directed CAR T cell therapy (murine CTL019 or humanized CTL119) at the Children's Hospital of Philadelphia who demonstrated repeated early CAR T cell loss or partial/no response to CAR T cell therapy received a PD-1 inhibitor starting no sooner than 14 days after CAR T cell infusion and after resolution of cytokine release syndrome (CRS) symptoms, with the possibility of repeated doses up to every 3 weeks.Results: Fourteen patients, ages 4-17 years, with heavily pretreated, relapsed B-ALL (n=13) or B lymphoblastic lymphoma (n=1), were treated with CD19-directed CAR T cell therapy (CTL019, n=4; or CTL119, n=10) in combination with pembrolizumab (n=13) or nivolumab (n=1). Three of 6 patients treated with CD19 CAR T cells in combination with a PD-1 inhibitor for early B cell recovery re-established B cell aplasia (a reflection of CAR T cell function) for 5-15 months, 2 of whom have persistent B cell aplasia with ongoing pembrolizumab therapy. Four patients started pembrolizumab for bulky extramedullary disease unresponsive to or relapsed after CAR T cells, with 2 partial and 2 complete responses seen. In one patient, significant CAR T cell proliferation was measured within days of starting pembrolizumab and in temporal correlation to radiographic disease response. In 4 patients who failed to achieve disease remission with initial CAR T cell infusion, no CRs were achieved with the addition of pembrolizumab, although partial responses were seen, and one patient progressed with CD19-dim/negative disease.CRS symptoms and fever typical of CAR T cell proliferative responses were observed in 3/14 patients within 2 days of starting pembrolizumab. Other early and delayed adverse effects associated with PD-1 inhibition were tolerable or reversible upon discontinuation, and including 1 case each of acute pancreatitis, hypothyroidism, arthralgias, urticaria, as well as 4 patients with grade 3-4 cytopenias. No grade 5 toxicities or graft-versus-host disease flares occurred. Two patients discontinued pembrolizumab for delayed adverse effects after multiple doses; both patients relapsed/progressed with CD19+ disease a few weeks after discontinuation.Discussion: T cell exhaustion or activation induced CAR T death (AICD) has been suspected to contribute to poor persistence of CAR T cells. We hypothesized that the PD-1 checkpoint pathway may be involved in CAR T cell exhaustion in some cases, which may be overcome by checkpoint inhibition. Here, promising responses were specifically seen in those with early B-cell recovery and bulky extramedullary disease. In contrast, PD-1 inhibition had partial, but no durable, effect in the four B-ALL patients with poor initial marrow response to CAR T cell therapy alone, suggesting a different mechanism such as AICD may be responsible for poor initial responses. No unexpected or fatal toxicities were seen. This cohort shows initial evidence that checkpoint inhibitors can be used effectively and safely with CAR T cell therapy in children with relapsed B-ALL, and that this strategy may augment CAR T cell effect and persistence. DisclosuresTeachey:Amgen: Consultancy; La Roche: Consultancy. Callahan:Novartis Pharmaceuticals Corporation: Consultancy. Porter:Genentech: Other: Spouse employment; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board. Lacey:Novartis Pharmaceuticals Corporation: Patents & Royalties; Tmunity: Research Funding; Parker Foundation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. June:Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties. Maude:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Cost-effectiveness of pembrolizumab in combination with chemotherapy in the 1st line treatment of non-squamous NSCLC in the US

Aims: To describe cost-effectiveness of pembrolizumab plus platinum and pemetrexed chemotherapy in metastatic, non-squamous, NSCLC patients in the US.Materials and methods: A model is developed utilizing partitioned survival analysis to estimate the cost-effectiveness of KEYNOTE-189 trial comparators pembrolizumab + chemotherapy (carboplatin/cisplatin + pemetrexed) vs chemotherapy alone. Clinical efficacy, treatment utilization, health utility, and safety data are derived from the trial and projected over 20 years. For extrapolating survival beyond the trial, a novel SEER population-data approach is applied (primary analysis), with separate estimation via traditional parametric extrapolation methods. Costs for drugs and non-drug disease management are also incorporated. Based on an indirect treatment comparison, cost-effectiveness of pembrolizumab + chemotherapy vs pembrolizumab monotherapy is evaluated for patients with programmed death-ligand 1 (PD-L1) ≥ 50%.Results: In the full non-squamous population, pembrolizumab + chemotherapy is projected to increase life expectancy by 2.04 years vs chemotherapy (3.96 vs 1.92), for an approximate doubling of life years. Resultant incremental cost-effectiveness ratios (ICERs) are $104,823/QALY and $87,242/life year. In patients with PD-L1 ≥ 50% and 1–49%, life expectancy is more than doubled (4.53 vs 1.88 years) and (4.87 vs 2.01 years), with a 32% (2.60 vs 1.97 years) increase in PD-L1 < 1% patients. Corresponding incremental costs/quality-adjusted life year (QALY) are $103,402, $66,837, and $183,529 for PD-L1 ≥ 50%, 1–49%, and <1% groups, respectively. Versus pembrolizumab monotherapy in PD-L1 ≥ 50% patients, representing current standard of care, pembrolizumab + chemotherapy increases life expectancy by 65% (4.53 vs 2.74 years) at an ICER of $147,365/QALY.Limitations and conclusions: The addition of pembrolizumab to chemotherapy is projected to extend life expectancy to a point not previously seen in previously untreated metastatic non-squamous NSCLC. Although ICERs vary by sub-group and comparator, results suggest pembrolizumab + chemotherapy yields ICERs near, or in most cases, well below a 3-times US per capita GDP threshold of $180,000/QALY, and may be a cost-effective first-line treatment for metastatic non-squamous NSCLC patients.

Addition of pembrolizumab to chemotherapy extends survival in advanced lung cancer

Addition of pembrolizumab to chemotherapy extends survival in advanced lung cancer

A randomized, double-blind phase II study of pembrolizumab versus placebo in patients with head and neck cancers at high risk for recurrence or low-volume residual disease: The PATHWay Study.

TPS6095 Background: Head and neck squamous cell carcinoma (HNSCC) is a major medical problem worldwide. While some patients may be cured with a combination of surgery, radiation, and systemic therapies, a significant percentage of patients will have recurrent and incurable disease. Despite our epidemiologic understanding of which patients are likely to recur, there are no consolidative therapies that have been shown to improve outcomes in this high-risk population. Pembrolizumab is a PD-1 inhibitor that has shown significant single agent activity in recurrent/metastatic HNSCC after treatment with other systemic therapies. While drug development of pembrolizumab is ongoing in Phase III studies in the 2nd and 1stline recurrent/metastatic disease settings, the ultimately the biggest potential impact based on patient volume and survival will potentially be in the curative intent setting. This randomized study is intended to explore the incorporation of pembrolizumab into the treatment of patients with locally advanced HNSCC at high risk for recurrence. Methods: Eligible patients must have HNSCC, completed therapy with definitive intent, and have an estimated risk of recurrence ≥40-50% (including tumors with extensive lymphadenopathy, extracervical lymphadenopathy, indeterminate residual local or distant mass after treatment, non-responders to induction chemotherapy, incomplete definitive therapy, receipt of salvage therapies, or oligometastatic disease treated definitively). Patients will be randomized to 1 year of either pembrolizumab 200 mg or placebo, administered intravenously day 1 of each 3-week cycle. The primary hypothesis of the study is that the addition of pembrolizumab will improve the 2-year progression-free survival (PFS) rate, compared to placebo. A sample size of 90 (45 patients per treatment arm, assuming 10% loss of follow up in N = 100 patient trial) will achieve 92.7% power at alpha = 0.10 (one-sided) to detect a difference between 50% and 72.5% PFS at 2 years. Approximately 51 events are required to detect such a difference. Patient screening and enrollment are expected to begin spring 2017.

A phase II study of pembrolizumab and docetaxel for aggressive RAI refractory thyroid carcinomas or salivary gland cancers: The iPRIME study.

TPS6099 Background: Both aggressive, radioactive iodine refractory thyroid cancers as well as high-grade salivary gland cancers respond poorly to chemotherapy, and there is no widely used standard of care. Targeted thearpies as well as cytotoxic chemotherapy (e.g. doxorubicin, or taxanes) are commonly used, but are only modestly effective. Both salivary gland and thyroid cancers have been shown to have tumor infiltrating lymphocytes, tumor inflammation, and PD-L1 expression ( Ayers, AACR 2015). Early data with anti-PD-1 immunotherapy using pembrolizumab (Keynote 28) show activity in ≤10a% of patients in a biomarker selected population (Keynote 28 thyroid and salivary gland cohorts). However, most patients are not PD-L1 positive and were not eligible. Recently synergy of anti-PD-1 checkpoint blockade with cytotoxic chemotherapy was reported in several studies (e.g. Langer et al, Keynote 21G) . Mechanistically chemotherapy may increase tumor inflammation, and eradicate immusupressive myeloid derived suppressor cells (MDSCs). Data suggest a significant increase in the response rate e. g. in KN21G from 29% to 55%. Furthermore the depths of responses and durability improve, including patients with PD-L1 negative tumors. Methods: We hypothesize that the combination of PD-1 checkpoint blockade and cytotoxic chemotherapy will show synergistic activity in aggressive thyroid cancers and salivary gland cancers. Eligible patients will have radioactive iodine refractory, aggressive thyroid cancer (cohort A, N = 25 pts), or progressive salivary gland cancers (cohort B, N = 25 pts). There will be no PD-L1 or other biomarker selection. Patients must have progressed on prior therapy. Patients will receive docetaxel at a dose of 75mg/m2 Q21 days as well as pembrolizumab 200mg flat-dose Q21 days intravenously. The primary outcome of this study is response rate. The addition of pembrolizumab to chemotherapy will increase the response rate from 20% (H0) to 40% (H1). A simon two-stage design will be used for each cohort (cohorts A and B) with an estimate 81% power in each arm. Patient screening and enrollment are expected to begin mid 2017. Clinical trial information: pending.

A 3D image-based quantification of immune cell-tumor spheroid interactions in the presence of checkpoint inhibition.

82 Background: Delivering on the promises of cancer immunotherapy is hampered by a lack of in vitro testing platforms that enable the early selection of promising drugs candidates. While quantification of the number of cytotoxic T cells and IFNγ secretion can give an indication of the drug effect, it is often critical to assess the functional cytotoxicity and infiltration capacity. In addition, immunomodulatory effects of drug combinations need to be carefully assessed before these treatment modalities reach patients. However there are unlimited possibilities of new combinations, especially in the view of synergy effects observed with double checkpoint inhibition blockade and combination with standard of care drugs. To specifically address the needs of immunotherapy cancer drug developers, we developed robust assays that incorporate the human immune system into tumor spheroid cultures, with functional read-outs in a high throughput (384well plate) format. Methods: Breast cancer cells were grown in a hydrogel to form 3D tumoroids. HLA-matched PBMCs with and without pre-activation/exhaustion were added and the infiltration of T cells and subsequent tumoroid killing was quantified. The effect of immune checkpoint blockade was also assessed with the addition of pembrolizumab. Quantification of effects of stimulators and checkpoint inhibition was achieved with 3D imaging and morphometric analysis with OMiner software. Results: Automated 3D image and data analysis enabled discrimination of immune-tumour cell interactions depending on activation status of T cells. Activated T cells more efficiently infiltrated and killed tumoroids than non-activated ones. Cytotoxic activity of overactivated/exhausted T cells was supressed but this could be reversed by the presence of checkpoint inhibitor in the coculture. Conclusions: A 3D environment allows the different cell types to engage in a more realistic setting than when cells are grow in a monolayer. Using image-based analysis, immune-tumor interactions can be dissected. This represents a new, highly powerful tool for cancer immunotherapy drug developers to select the most promising compounds, allowing faster progression towards the clinic.

Abstract OT2-01-03: Phase II Trial of the addition of pembrolizumab to letrozole and palbociclib in patients with metastatic estrogen receptor positive breast cancer who have stable disease on letrozole and palbociclib

Abstract Background: The combination of palbociclib and letrozole has become the standard of care for patients with newly diagnosed estrogen receptor positive (ER+) metastatic breast cancer (MBC), with promising prolongation of progression free survival (PFS). However, nearly half of all patients achieved stable disease only after the first 6 months of therapy. Check-point inhibitor pembrolizumab was effective in ER+ MBC with a response rate of 13-17%, this study will evaluate the efficacy of adding pembrolizumab for patients with ER+ MBC who have achieved stable disease (SD) on letrozole and palbociclib. Trial Design:This is an open-label single institutional study. Patient will receive letrozole (2.5 mg) once a day and palbociclib (125 mg, 100 mg, or 75 mg as established tolerated dose) once a day for 3 weeks on and 1 week off. Pembrolizumab will be given at 200 mg IV every 3 weeks. Eligibility Criteria: Eligible patients must be postmenopausal women with ER+ MBC with measurable disease by RECIST1.1, ECOG performance status 0-1; must have received letrozole and palbociclib for at least 6 months, and have documented SD per RECIST 1.1. Up to3 lines of previous systemic therapy including endocrine therapy and/or chemotherapy are allowed. Patients are excluded if they had prior treatment with anti--PD1 or anti-PD-L1therapy, immunodeficiency; currently using systemic steroids active tuberculosis infection; major surgery within 28 days; active or untreated CNS metastases; history of interstitial lung disease; active infection requiring systemic therapy; or active cardiac disease. Specific Aims: The primary objective is to evaluate the objective response rate(ORR). The secondary objective is to determine the safety and tolerability of pembrolizumab plus the letrozole/palbociclib combination. We will use clinical benefit rate (CBR), duration of response (DOR), PFS, and OS to test the efficacy of this novel drug combination. Statistical Design: We will employ a three-at-risk design (modified rolling design) for the initial cohort of this Phase II study to insure the triplet is well-tolerated. This design permits only 3 patients to be a risk for DLT at any one time during the “safety lead-in” .When the first 6 patients have completed the observation period and treatment with ≤1 DLT, the safety lead-in for the triplet will be considered successful, and accrual will proceed to a total of 18 patients. Response (CR or PR by RECIST version 1.1) in patients who have demonstrated only SD on letrozole and palbociclib can be reasonably attributed to the addition of pembrolizumab. As a result, we set the probability of a response occurring without the addition of pembrolizumab as 3% or less. With 18 patients, a true response rate of 20% would result in at least 2 responders with 90% power and a type I error of 10%. With 18 patients, the response can be estimated with a 95% CI half-width of 23%. Target Accrual: 18. Citation Format: Yuan Y, Frankel P, Synold T, Yost S, Lee P, Waisman J, Somlo G, Hurria A, Mortimer J. Phase II Trial of the addition of pembrolizumab to letrozole and palbociclib in patients with metastatic estrogen receptor positive breast cancer who have stable disease on letrozole and palbociclib [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-03.

Checkpoint Inhibitor-Induced Colitis: A New Type of Inflammatory Bowel Disease?

Checkpoint inhibitors are immune-stimulatory antibodies that have transformed the management and prognosis of individuals with metastatic melanoma and other cancers. Checkpoint inhibitor–induced colitis is an increasingly recognized immune-related adverse event that shares many of the same phenotypical, serological, and histological characteristics of both Crohn’s disease and ulcerative colitis, suggesting that checkpoint inhibitor–induced colitis may represent a new inflammatory bowel disease phenotype. We report a 73-year-old man with metastatic melanoma who developed ipilimumab-induced colitis with subsequent transformation to Crohn?s colitis-like phenotype after the addition of pembrolizumab.

Abstract 4864: Engaging the immune system with GSK3174998, a potent anti-OX40 agonist antibody

Abstract Introduction: GSK3174998, a humanized IgG1 agonistic anti-OX40 monoclonal antibody (mAb) identified in collaboration between GSK and MDACC is currently in Phase I clinical development. Critical for the development of more effective cancer immunotherapy are agents that stimulate effector T cells (Teff) and inhibit the immunosuppressive function of regulatory T cells (Treg) that typically infiltrate tumors. OX40 is a tumor necrosis factor receptor superfamily member expressed on the surface of activated CD4+ and CD8+ T cells. OX40 agonism stimulates both immune effector and memory functions and attenuation of Tregs. Therefore, OX40 agonistic mAbs are ideal candidates to potentially increase the efficacy of immune-checkpoint blocking antibodies, like anti-PD1 (aPD1). Methods: GSK3174998 has suitable cross-reactivity to cynomolgus monkey OX40 to inform directly on toxicology, pharmacokinetic and pharmacodynamic (PD) preclinical endpoints. However, to understand the antitumor efficacy of OX40 agonism in vivo, studies were performed using a surrogate mAb to murine OX40 (OX86) alone or in combination with a surrogate aPD1 antibody in A20 lymphoma and CT26 colon carcinoma syngeneic tumor models. Intratumoral (i.e. tumor infiltrating T cells) and peripheral (blood) PD biomarkers, including T cell intracellular and surface protein expression, cytokine production and gene regulation were analyzed. Results: GSK3174998 was well tolerated in monkeys up to 100 mg/kg. In vitro T-cell activation of OX40 with GSK3174998 resulted in enhanced CD4+ and CD8+ effector T-cell proliferation, both in plate-bound as well as soluble PBMC assays. Suppression of Treg differentiation was observed with GSK3174998 as compared with an Fc-disabled mAb, which did not demonstrate these effects. In vitro GSK3174998 induced Th1 cytokine production (IFN and TNFá) and this was further enhanced by the addition of pembrolizumab. In vitro OX86 demonstrated similar characteristics to GSK3174998. In vivo OX86 induced a significant dose-dependent, durable anti-tumor response as monotherapy, which was significantly enhanced when combined with an aPD1 checkpoint inhibitor. Preclinical efficacy correlated with PD changes in several immunological markers including T-cell proliferation and activation. In silico and IHC analysis of expression of OX40 and PDL1 in human tumors was utilized to prioritize cancers most likely to respond to monotherapy and combination therapy for the first-time-in-human (FTIH) clinical study. Conclusions: GSK3174998 is a potent anti-OX40 agonist that engages the immune system via several T-cell-mediated pathways and may further enhance the antitumor activity observed with PD1 inhibition. Preclinical studies provide a strong rationale to support the ongoing FTIH Phase I study of GSK3174998 administered alone and in combination with pembrolizumab to patients with selected advanced solid tumors. Citation Format: Carlo Toniatti, Niranjan Yanamandra, Kui Voo, Amin Al-Shami, Laura Bover, Peter Morley, Sara Brett, Tim Lofton, Jennifer Greer, Ningping Feng, Ignacio Ivan Wistuba, Sabyasachi Bhattacharya, Christopher Hopson, David Kilian, Heather Jackson, Paul Bojczuk, Mili Mandal, Junping Jing, Kevin French, Roopa Srinivasan, Axel Hoos. Engaging the immune system with GSK3174998, a potent anti-OX40 agonist antibody. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4864.