Immuno-oncology Agents Research Articles

Abstract 1626: PMC309, a highly selective anti-VISTA antibody enhances T cell activation through blocking the interaction of T cells and myeloid derived suppressor cells (MDSC)

Abstract TME (tumor microenvironment) consists of blood & lymphatic vessels, stromal cells, and immune cells such as lymphocytes, macrophages, and antigen-presenting cells (APC). Cellular interactions among various immune cell types within TME regulate tumor growth, metastasis, and resistance to cancer therapy. V-domain Ig suppressor of T cell activation (VISTA) is a negative checkpoint regulator highly expressed on tumor-infiltrating myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAMs) and VISTA blockade could enhance antitumor immunity in TME. PMC-309 binding to VISTA expressing cells is highly selective and the selectivity is maintained even in the low pH conditions that mimic TME. Binding of PMC-309 on MDSC cells enhances the secretion of IFN-γ, TNF-α, and IL-2 in Mixed Lymphocyte Reaction (MLR) settings. In in vivo study, PMC-309 suppressed tumor growth, which was further attenuated with an anti-PD1 antibody. The anti-tumor activity was associated with enhanced T cell activation, increased secretion of pro-inflammatory cytokines, and increased penetration of tumor-infiltrating leukocytes (TIL) into TME. Patients who became resistant to anti-CTLA-4 and anti-PD(L)1 antibody showed increased expression of VISTA, suggesting that anti-VISTA therapeutics can help to treat the patients who do not respond well to other immuno-oncology drugs. We are developing PMC-309 as a next generation immuno-oncology (IO) agent, which can convert immunologically cold into hot tumors as a mono- or combo- therapy with other IO agent. Citation Format: Cheon Ho Park, Sang Soon Byun, Jin Yong An, Sun Hyung Ha, Hye Rim Han, Nu Ri Kang, Beom Yong Park, Eun Ah Lee, Hyun Sun Park, Jin-San Yoo, Weon Sup Lee. PMC309, a highly selective anti-VISTA antibody enhances T cell activation through blocking the interaction of T cells and myeloid derived suppressor cells (MDSC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1626.

SY17-4 Immuno-oncology agents for advanced gastric cancer

The treatment of metastatic gastric adenocarcinoma remains challenging. The management typically consisted of the use of combination cytotoxic agents in various lines of treatment, trastuzumab in combination with chemotherapy in the first line treatment of HER2 positive gastric adenocarcinoma and ramucirumab ± paclitaxel in the second line treatment. Recently progress has been made in the management of gastric cancer with the introduction of the anti-PD antibodies nivolumab and pembrolizumab. The data on nivolumab and pembrolizumab ± chemotherapy in first line and in pretreated and/or chemorefractory are interesting and open perspectives for improved outcome and for prolonged survival in selected patients. The introduction of the anti-PD antibodies will shape our new treatment algorithms and guidelines. Optimal clinical and molecular selection is necessary in order to optimize the use of these checkpoint inhibitors. The data on the selection for CPI through predictive biomarkers, such MSI-H/MSS status, PDL CPS scoring, EBV staining and TMB are important to the use of CPI. The various situations and indications, in which CPI have been and are still studied will be discussed: early lines of treatment of metastatic gastric cancer, pretreated and chemorefractory and maintenance treatment. In the future the anti-PD/anti-PDL antibodies may be combined with other immuno-oncology agents, such as CTLA-4 antibodies and new classes of immuno-oncology agents, but also with other targeted agents such as e.g. anti-HER2 targeting agents and PARP inhibitors.

Abstract 2926: CT26.WT-luc orthotopic syngeneic tumor model of colon cancer: development and immunotherapy response

Abstract Colorectal cancer (CRC) is a major contributor to the whole of cancer as a disease, representing 10% of all cases of cancer. Recent clinical studies and FDA approvals demonstrate strong possibilities for the future of immunotherapy in the treatment of CRC. Highly translational preclinical models of the disease are required to assess the effectiveness of novel immuno-oncology agents. The CT26.WT murine colon carcinoma model is a widely used syngeneic tumor model to evaluate the preclinical efficacy of immuno-oncology agents. Subcutaneous tumor models are limited in translatability compared to the orthotopic implant site including differential stromal interactions, immune cell infiltrate, and response to immunotherapy. We present the development of a robust murine orthotopic colon tumor model (CT26.WT-luc) assessed by bioluminescence imaging (BLI) and assessed for response to common checkpoint targets. All animal work was performed in an AAALAC accredited facility, in alignment with applicable animal welfare regulations and with predetermined humane euthanasia criteria on all studies. Subcutaneous CT26.WT-luc tumors were dissected into fragments and grafted onto the cecum of naïve Balb/c mice. Mice were subjected to BLI twice weekly for four weeks for longitudinal monitoring of tumor growth. The tumor engraftment rate was 95% based on BLI and necropsy, no spontaneous regressions were observed. The BLI derived tumor volume doubling time was 1.5 days and the median time on study was 21 days. Common clinical observations associated with disease progression were abdominal distension due to tumor growth and bodyweight gain. Necropsy revealed large primary masses attached to the cecum with large vascular involvement, and small nodules on the liver and abdominal wall. To assess the model response to immunotherapy, Balb/c mice bearing orthotopic CT26.WT-luc tumors were treated by intraperitoneal administration of 10mg/kg isotype control, anti-PD-L1, anti-CTLA-4 or anti-PD-1 twice weekly for two weeks (Bio X Cell). Administration of anti-PD-L1 resulted in one complete regression. Anti-CTLA-4 treatment resulted in a day 23 ΔT/ΔC of 0.1% and five partial regressions with no visibly detectable disease at necropsy. Administration of anti-PD-1 did not result in regressions or tumor free survivors. Administration of either anti-PD-L1 or anti-CTLA-4 provided an increase of life span over isotype control of 13 and 24 days, respectively. Terminal necropsy revealed no evidence of tumors or other lesions in 1 out of 8 animals administered anti-PD-L1, and 5 out of 8 animals administered anti-CTLA-4. This model represents a powerful tool with translational potential for assessing the efficacy of novel immune modulating agents with the possibility of combination therapy. Assessment of tumor response, cell and molecular differences between subcutaneous and orthotopic CT26.WT-luc tumors is ongoing. Citation Format: Patrick Allison, Derrik Germain, Meredith Baugher, Maryland Franklin. CT26.WT-luc orthotopic syngeneic tumor model of colon cancer: development and immunotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2926.

Abstract 2711: Modeling pancreatic and non-small cell lung cancer using a humanized mouse platform

Abstract The development of immuno-oncology agents against human targets is actively pursued in the preclinical space using immune deficient mice with reconstituted human immune systems. We utilized a human peripheral blood mononuclear cell (hPBMC) based humanized mouse model to investigate treatment response in human pancreatic and non-small cell lung cancers. Three human PBMC donors were identified that exhibited consistent T cell engraftment, allowing for a four-week treatment window, and robust growth of two human xenograft models in NSG mice, MiaPaCa-2 (pancreatic) and A549 (non-small cell lung). Anti-tumor efficacy of pembrolizumab (Keytruda®) targeting human PD-1 was also assessed in these humanized models. All animal work was performed in an AAALAC accredited facility, in alignment with applicable animal welfare regulations and with predetermined humane euthanasia criteria on all studies. Control growth of MiaPaCa-2 and A549 tumors were similar with and without hPBMC engraftment. Both tumor models progressed uniformly to a mean tumor volume of 1000 mm3 without apparent hPBMC impact. Engraftment was assessed at 28 and 38 days (MiaPaCa-2) or 42 days (A549) after hPBMC administration by immunophenotypic analysis using flow cytometry in peripheral blood. At all timepoints, hCD45+ cells were detected. While intragroup variability occurred, engraftment remained constant or increased over time. hPBMC engraftment was reproducibly higher for animals harboring A549 compared to MiaPaCa-2 tumors, with hCD45+ cells in blood ranging from 31-52% and 19-33% of total live cells, respectively. It is unknown if this was a result of normal variability or whether this finding is model dependent. Pembrolizumab treatment in the hPBMC-engrafted mice did not inhibit A549 or MiaPaCa-2 tumor growth under the conditions tested (median ΔT/ΔC of 76-118% (Day 41) and 60-106% (Day 22), respectively). However, in vitro, CD8+ T cells from all donors responded to CD3/CD28 stimulation, demonstrating at least 36-fold upregulation of the Ki67 proliferation marker and at least 9-fold upregulation of interferon gamma release, indicative of cytotoxic activity. This result indicated that the hPBMCs were healthy and responsive, but the extent of activation varied by donor. Investigation of human T cell infiltration into human tumors following treatment with pembrolizumab are currently being performed. Despite the lack of response of pembrolizumab against A549 or MiaPaCa-2, these models are promising translational tools for assessing efficacy of novel therapeutics using rational combination strategies with pembrolizumab. This humanized mouse model represents a powerful preclinical platform to examine the effects of novel agents that harness human T cells to direct anti-tumor activity both as monotherapy and in combination with FDA approved or investigational agents. Citation Format: Sheri Barnes, David Draper, Stacey Roys, Philip Lapinski, Maryland Rosenfeld Franklin. Modeling pancreatic and non-small cell lung cancer using a humanized mouse platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2711.

Metastasis-directed radiation therapy after radical cystectomy for bladder cancer

PurposeMetastasis-directed radiation therapy (MDRT) may improve oncologic and quality of life outcomes in patients with metastatic cancer, but data on its use in metastatic bladder cancer is severely limited. We sought to review our institutional experience with MDRT in patients with metastatic bladder cancer following radical cystectomy. Materials and MethodsWe reviewed records of patients who underwent radical cystectomy and subsequent MDRT at our institution between 2009 and 2020. Baseline demographic and clinical/pathologic factors were collected, as were details of treatment including systemic therapy and MDRT. Cases were categorized by treatment intent as consolidative (intended to prolong survival) and palliative (intended only to relieve symptoms). Response to treatment, survival, and toxicity outcomes were reviewed. ResultsA total of 52 patients underwent MDRT following radical cystectomy. MDRT was categorized as consolidative in 40% of cases and palliative in 60%. Toxicity (CTCAE Grade ≥ 2) was reported in 15% of patients, none of which exceeded Grade 3. Most patients undergoing consolidative MDRT were treated with SBRT techniques (76%) and a majority (67%) received concurrent treatment with an immuno-oncology agent. Among patients treated with consolidative intent, 2-year progression-free and overall survival were 19% and 60%, respectively. ConclusionMDRT is safe and well-tolerated by a majority of patients. A majority of patients treated with consolidative intent survived ≥ 2 years from treatment.

Highly Multiplexed Imaging Mass Cytometry Allows Visualization of Tumor and Immune Cell Interactions of the Tumor Microenvironment in FFPE Tissue Sections

Background: Cancer immunotherapy, and checkpoint inhibition in particular, is poised to radically transform our approach to treating cancer. Recent clinical successes with checkpoint inhibitors and immuno-oncology agents have demonstrated the importance of the immune system in controlling and treating cancers. Early indications that tumor cells can generate an antitumor immune response were evidenced by the varying degrees of immune cell infiltration found in the tumor microenvironment (TME). Despite the presence of this immune infiltrate, it has long been suspected that immune function is defective or inhibited by the TME. The rapid series of new drug approvals in diverse tumors ranging from melanoma, kidney, lung, bladder and Hodgkin lymphoma show that the anti-tumor immune responses can be activated for clinical benefit, however, our understanding of the mechanics of immune response to immuno-oncology agents has lagged behind the clinical successes. Furthermore, responses to immuno-oncology agents are not universal and mechanisms of resistance are poorly described. In large part, this is due to limitations of currently available technology which does not allow for detection of complex immunophenotypes in tissue sections. High parameter methods such as gene expression profiling or flow cytometry have been applied to study the TME, however data on cellular heterogeneity and rare cells is lost with gene expression studies and the spatial relationship between tumor and immune cells is lost with flow cytometry. The Fluidigm Hyperion imaging mass cytometry (IMC) system combines a CyTOF mass cytometer with a laser ablation system allowing for 40+ parameter simultaneous immunophenotyping on a single slide of FFPE tissue, with sub-cellular resolution. Here we describe our efforts to develop and optimize highly multiplexed assays for the characterization of immune cells in the TME in various tumors on the IMC platform.Methods: Literature was reviewed to identify markers relevant to TME. Metal conjugated antibodies were obtained from Fluidigm, and supplemented with custom conjugations where required. Antibodies were validated on FFPE tissue sections of lymphoma, colon cancer, and normal lymph node as controls. Antigen retrieval, blocking, and antibody staining concentrations were optimized to identify universal staining conditions. Membrane and nuclear/DNA staining was performed to aid in cell segmentation. Slides were imaged using the Fluidigm Hyperion IMC system with a 1µM laser ablation spot size and frequency of 100-200 Hz. Area of analyzed tissue varied from 400 um2 up to 1000 um2 with multiple areas imaged per specimen. Image analysis was performed with MCD viewer (Fluidigm) or CellProfiler/miCAT (https://doi.org/10.1101/109207).Results: We successfully performed IMC imaging of normal lymph nodes (LN), colon cancer, Hodgkin lymphoma, NK lymphoma by using a 26 parameter panel. We were able to clearly identify tissue architecture in the normal lymph node, germinal center (GC), mantle zone(MZ), cortex/paracortex(PC) (Fig. 1A), and with enough resolution to observe three way interaction between CD4+ T cell, CD8+ T cell and CD68+ antigen presenting cell (Fig. 1B). In tumors we were able to characterize specific populations such as CD8+Tcells, Th1/Th2 subsets, FoxP3+Treg, tissue associated macrophages, CD56+NK cells and tumor vasculature. Important immuno-oncology targets such as LAG3, PDL1/PDL2 and PD1 were measured. Tertiary lymphoid structures in colon cancer were found to have abundant FoxP3+Treg (Fig. 1C). In Hodgkin lymphoma we were able to observe tumor [Reed Sternberg (RS) cells], effector and regulatory cell interactions at a single cell level. CD8+ cells (green) adjacent to RS cell are flanked by immunosuppressive TREG (FoxP3-teal) and Th2 (CCR-yellow) cells (Fig. 1D).Conclusion: IMC allows for successful multiplex imagining of the TME in FFPE tissues. The method does not require special processing and can be applied to archival specimens and tumor microarrays. Methods developed here should be applicable for the study of the TME in other tumor types and could be used to identify additional biomarkers of response to immuno-oncology agents. [Display omitted] DisclosuresMerchant:Fluidigm, Inc: Research Funding; Pfizer, Inc: Consultancy, Research Funding.

Duration of Treatment of Multiple Myeloma Regimens in Patients with Relapsed or Refractory Multiple Myeloma: Findings in US Clinical Practice Settings

Introduction: Many new treatments and combinations have emerged over the last decade to treat relapsed or refractory multiple myeloma (RRMM). Treatment strategies include doublet and/or triplet combinations from the following classes of agents: immunomodulatory drugs, proteasome inhibitors, and recently approved immuno-oncology agents. Combinations with new agents like pomalidomide, carfilzomib, ixazomib, elotuzumab, and daratumumab have demonstrated improved survival in RRMM in clinical trials, specifically with continued treatment until disease progression, with an acceptable safety profile (Lonial S et al. N Engl J Med 2015; Dimopoulos M et al. N Engl J Med 2016; Palumbo A et al. N Engl J Med 2016; Moreau P et al. N Engl J Med 2016; Stewart AK et al. N Engl J Med 2015; Dimopoulos M et al. Blood 2012). Median duration of treatment (DoT) was described in the literature as 12.4 wk for pomalidomide plus low-dose dexamethasone, 68 wk for ixazomib plus lenalidomide/dexamethasone, 74 wk for elotuzumab plus lenalidomide/dexamethasone, and 88 wk for carfilzomib plus lenalidomide/dexamethasone (Lonial S et al. N Engl J Med 2015; Moreau P et al. N Engl J Med 2016; Stewart AK et al. N Engl J Med 2015; Dimopoulos M et al. Blood 2012). The actual DoT of these agents in clinical practice settings is not known and it is unclear if DoT is affected by safety concerns and/or might have an impact on patient (pt) outcomes. Here we provide real-world evidence of DoT and time to next therapy (TTNT) with each of these agents in an attempt to understand their potential for durability of response and tolerability.Methods: Analysis was conducted using the Explorys electronic medical records US database. Pts aged ≥18 y with ≥1 medical record with a diagnosis of MM (International Classification of Diseases [ICD], Ninth Revision, Clinical Modification diagnosis codes: 203.0x; ICD-10 codes: C90.0x) any time from January 1, 2010, preceded by ≥12 mo (baseline period) without a diagnosis of MM, were identified and followed longitudinally from their index diagnosis date (index date) through the course of available follow-up. A line of therapy (LoT) was defined as a drug/drug combination taken within a 28-d period from initiation of treatment course and ended upon cessation of those drugs, or at initiation of a drug not part of the current LoT. Pts with RRMM were identified as those who had ≥1 prior LoT. Demographic and baseline characteristics were analyzed using descriptive statistics. Distribution of treatment regimens in each LoT are reported; treatment cohorts are not mutually exclusive and LoTs containing multiple drugs are included in respective cohorts. Median DoT in each LoT and TTNT were estimated using descriptive and Kaplan-Meier analyses.Results: 1745 LoTs were identified for 854 pts with RRMM (median age 66 y; 51% male; 37% had hypertension; 10% had chronic pulmonary disease at baseline). LoTs comprised pomalidomide (n=567 [32%]), carfilzomib (n=609 [35%]), ixazomib (n=172 [10%]), elotuzumab (n=76 [4%]), and daratumumab (n=321 [18%]). These agents were mostly used in later LoTs (mean number of prior LoTs, 3.7). Median (IQR) follow-up from index date was 39.4 mo (25.5-56.4) for these pts. Baseline characteristics were similar across treatment cohorts, although pts receiving ixazomib and carfilzomib presented with higher rates of hypertension and chronic pulmonary disease at baseline (Table). Mean/median DoT for pts with a second line (2L) of treatment and pts with ≥2L was longest for elotuzumab (8.7/4.4 mo and 5.3/2.7 mo, respectively). Kaplan-Meier estimates supported these findings (Table). Mean/median TTNT for pts with 2L or ≥2L was longest for elotuzumab (2L: 9.6/6.5 mo; ≥2L: 6.1/3.7 mo) and carfilzomib (2L: 8.7/6.2 mo; ≥2L: 7.3/4.7 mo).Conclusions: Real-world evidence indicates that the new agents for RRMM-pomalidomide, carfilzomib, ixazomib, elotuzumab, and daratumumab-are used in later LoTs. DoT in clinical practice may be shorter than that reported in clinical trials. Rates of remaining on treatment were highest among pts treated with elotuzumab, suggesting that the longest durability of response observed with this immuno-oncology agent may be accompanied by acceptable tolerability despite longer exposure to treatment. Additional analyses and follow-up will determine whether longer DoT improves clinical outcomes.Study support: Bristol-Myers Squibb. [Display omitted] DisclosuresPotluri:SmartAnalyst Inc.: Employment; Janssen: Consultancy, Research Funding. Kanakamedala:SmartAnalyst Inc.: Employment. Chen:Bristol-Myers Squibb: Employment. Yasenchak:Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy. Ranjan:SmartAnalyst India Pvt. Ltd: Employment. Papademetriou:SmartAnalyst Inc.: Employment. Bhandari:SmartAnalyst India Pvt. Ltd: Employment. Mann:SmartAnalyst India Pvt. Ltd: Employment. Davis:Bristol-Myers Squibb: Employment.

Treatment Patterns and Associated Outcomes in Patients with Relapsed or Refractory Multiple Myeloma in the US and Non-US Countries: Findings from Preamble

Introduction: The management of multiple myeloma (MM) has undergone profound changes over the recent past due to newer therapeutic agents with novel mechanisms of action and refinement of treatment strategies. Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and 3-drug regimens involving a PI and an IMiD (PI+IMiD) have become standards of care in MM. The immuno-oncology (I-O) agents elotuzumab and daratumumab were approved to treat relapsed or refractory (RR) MM by the US Food and Drug Administration in 2015, and by the European Medicines Agency in 2016. Extension of survival for patients with MM is a realistic goal, although access to therapies may vary between the US and non-US countries. Comparison of treatment patterns and associated outcomes for patients with RRMM in the US with non-US countries will shed light on the impact of treatment access on patient outcomes.Methods:Patients from the US and 5 non-US countries (Canada, France, Germany, Italy, and UK), ≥18 y of age with RRMM, ≥1 prior systemic therapy, and initiating treatment with a PI, an IMiD, a PI+IMiD combination, or an I-O agent within 90 d before or 30 d after study consent, were identified from PREAMBLE, an ongoing, prospective, non-interventional observational study (NCT01838512). Patient data were collected at each healthcare provider visit over a 3-y period or until the end of patient follow-up. Statistical comparisons were made using t tests and Mann-Whitney U tests for continuous variables and chi-square tests for categorical variables; 2-sided p-values were obtained. Overall survival (OS) was analyzed using Cox regression and Kaplan-Meier techniques.Results: 1075 patients with RRMM (median age 69 y; 57.2% male) were enrolled; 341 (31.7%) from the US and 734 (68.3%) from non-US countries. At data cut-off (May 27, 2017), 522 (48.6%) patients had withdrawn from the study; 357 (68.4%) of patients who had withdrawn had died, mainly due to disease progression. Median follow-up was 18.7 mo (interquartile range: 8.8-31.5 mo). Patients from the US and non-US countries were similar with regard to sex, disease status, and International Staging System stage, although compared with patients from non-US countries, patients from the US were younger at baseline, had more comorbidities, and received more prior lines of treatment (Table).The proportion of patients receiving treatment in a subsequent line was similar between the US and non-US countries (54.3% vs 54.8%). Significantly more patients from the US received 2 or more subsequent therapies than patients from non-US countries (63.6% vs 53.4%; p=0.007). In addition, compared with patients from non-US countries, patients from the US were significantly more likely to receive I-O agents (8.2% vs 1.2%, p<0.001), and all newer agents (37.5% vs 13.4%, p<0.001), including the I-O agents elotuzumab and daratumumab, the PIs carfilzomib and ixazomib, the IMiD pomalidomide, and the histone deacetylase inhibitor panobinostat.Median OS was longer for patients from the US than for patients from non-US countries (32.0 vs 28.6 mo), although the difference was not statistically significant (p=0.831). After adjusting for baseline differences between the US and non-US countries, mortality among patients from non-US countries was 30% higher than among patients from the US (hazard ratio 1.30; 95% CI 0.94-1.80; p=0.108).Conclusion: This pilot analysis of data from a clinical setting shows that patients with RRMM in the US had greater access to newer agents and received more subsequent therapies than patients in non-US countries. The longer OS in patients from the US may suggest clinical benefit associated with newer agents. Future analysis may be necessary to validate our findings.Study support:Bristol-Myers Squibb. [Display omitted] DisclosuresVij:Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy; Takeda, Onyx: Research Funding. Chen:Bristol-Myers Squibb: Employment. Popov:Parexel: Employment. Durie:Johnson & Johnson: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Glycomimetcs: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zyczynski:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment. Goldschmidt:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Chugai: Consultancy, Honoraria, Research Funding, Speakers Bureau; Morphosys: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau.

Healthcare Resource Utilization and Costs Associated with Different Treatment Modalities of Relapsed/Refractory Multiple Myeloma Patients in the US: Findings from Preamble

Introduction: Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and treatments involving both a PI and an IMiD (PI+IMiD) are the principal therapies for treating relapsed/refractory multiple myeloma (RRMM). The immuno-oncology (I-O) agents elotuzumab (elo) and daratumumab (dara) may bring new and promising solutions to patients (pts). The adoption of these treatments may come with high healthcare resource utilization (HCRU) and costs. It is important to further understand HCRU by different treatment modalities in real-world practice settings. Here we evaluate HCRU and costs in pts receiving different treatment modalities for RRMM.Methods: PREAMBLE is an ongoing, prospective, multinational, noninterventional observational study (NCT01838512). Pts ≥18 y of age with RRMM, ≥1 prior therapy, and who initiated treatment (index therapy) with a PI (including carfilzomib [carf], bortezomib [bort], and ixazomib), an IMiD (including lenalidomide [len], pomalidomide [pom], and thalidomide), an IMiD+PI combination, or I-O agents within 90 d before or 30 d after study consent were identified. Pt data were collected at each healthcare provider (HCP) visit, over 3 y or until the end of pt follow-up, including clinic/physician office visits, emergency room (ER) visits, hospital outpatient visits, hospitalizations, and home healthcare/other visits. Demographic and baseline characteristics were analyzed using descriptive statistics. The median duration of treatment (mDoT) was estimated using Kaplan-Meier (K-M) methods. HCRU was estimated using the mean number of incidents, per-1000-patients-per-month (1000 PPM) metric in a period up to 12 mo from start of index therapy (index date).Results: 341 pts (median age 67 y; 59% male) were enrolled in the US. At the time of data cut-off (May 27, 2017), 187 (55%) had withdrawn from the study; 117 (63%) of the withdrawn pts had died. Median (range) follow-up was 11.8 mo (<0.1, 41.2). At study entry, 30 pts were receiving I-O agent-based index therapy (dara, n=26; elo, n=4). Pts were divided into 4 cohorts based on index therapy: dara (26/337, 8%), PI (n=174, 52%; carf 92/174; bort 80/174), IMiD (n=75, 22%; pom 31/75), and IMiD+PI (n=62, 18%; bort+len 35/62). The 4 treatment cohorts were similar in sex, race, disease status, International Staging System stage, and comorbidities, although pts on dara received significantly more prior therapies than those on other treatments (Table). Of the 26 pts on dara, 31% (n=8) were still on treatment at the time of data cut-off, and of those who discontinued index therapy (n=18, 69%), 61% (n=11) were due to disease progression, which was higher than for other treatments (p=0.0468). The K-M estimate of mDoT for pts on dara was 4.2 mo, similar to that for PI (4.1 mo) but shorter than for other treatments (p=0.0305). In the PI cohort, carf had a shorter mDoT than bort (3.4 vs 5.2 mo). Of 3093 HCP visits overall, the most common type was clinic/physician office visits (n=2649, 86%), followed by ER visits/hospitalizations (n=233, 8%), and hospital outpatients (n=164, 5%). Per 1000 pts treated, pts receiving PI+IMiD had the most HCRU visits in a 1-mo period, vs least for dara (mean 1000 PPM: 1619 vs 1013 visits). This was also true for clinic/physician office visits and hospital outpatients (Table). Notably, mean 1000 PPM ER visits/hospitalizations were higher for pts receiving dara than for any other treatment (n=181, 18%). Among pts receiving a PI, those on carf had higher mean 1000 PPM total visits (n=1001) than those on bort (n=710); this remained true for each of the healthcare resource categories investigated in this study.Conclusions: Routine management of RRMM and treatment-related events drive HCRU, which may differ by treatment. This preliminary analysis suggests that pts on dara appear to have shorter mDoT and fewer outpatient visits, but more ER visits and hospitalizations, compared with pts on other treatments. Receiving carf appears to be associated with more HCRU visits overall, and for each of the healthcare resource categories compared with bort. The study is ongoing and further analysis will be necessary to better understand HCRU patterns observed with these new treatment modalities in clinical practice settings.Study support: Bristol-Myers Squibb. [Display omitted] DisclosuresKuter:Fujifilm: Consultancy; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees; ONO: Consultancy; 3SBIO: Consultancy; Protalex: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Merck: Consultancy; Syntimmune: Consultancy, Research Funding; Pfizer: Consultancy; Novartis: Consultancy; Zafgen: Consultancy; Genzyme: Consultancy; Shire: Consultancy, Research Funding; Amgen: Consultancy; Alexion: Consultancy, Research Funding; Argenx: Consultancy. Chen:Bristol-Myers Squibb: Employment. Popov:Parexel: Employment. Davis:Bristol-Myers Squibb: Employment. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy.

Artificial intelligence-powered spatial analysis of tumor infiltrating lymphocytes (TIL) to reflect target gene expressions of novel immuno-oncology agents.

e14534 Background: Novel immuno-oncology (IO) agents are promising but showing their efficacy in early phase clinical trials has been challenging due to limited enrichment strategies using practical biomarker platforms. We hypothesize that an artificial intelligence (AI)-powered spatial analysis of TIL using practically feasible H&amp;E slides, can reflect a specific target gene expression derived from RNA sequencing. This enhances its potential application in early development of novel IO agents. Methods: An AI-powered spatial TIL analyzer, namely Lunit SCOPE IO, was developed with data from 2.8 x 109 micrometer2 H&amp;E-stained tissue regions and 5.9 x 106 TILs from 3,166 whole slide images of multiple cancer types, annotated by board-certified pathologists. Inflamed Score and Immune-Excluded Score was defined as the proportion of all tumor-containing 1 mm2-size tiles within a WSI classified as being of inflamed immune phenotype (high TIL density within cancer epithelium) and immune-excluded phenotype (low TIL density within cancer epithelium, but high TIL density within stroma), respectively. We used RNA sequencing data and H&amp;E images from The Cancer Genome Atlas database, excluding those of mesenchymal origin (n = 7,467). Spearman's rank correlation between each gene expression and IS or IES, respectively, was calculated. Correlation coefficient &gt; 0.2 and false discovery rate (FDR) &lt; 1% was considered as a significant correlation. Results: In a total of 20,304 genes, 871 (4.3%) and 1,155 (5.7%) genes were significantly correlated with Inflamed Score (IS) and Immune-Excluded Score (IES), respectively. The IS was highly related to genes reflecting immune cytolytic activity and targets of approved immune checkpoint inhibitors (Table). Interestingly, it was also significantly correlated with target genes of novel IO such as TIGIT, LAG3, TIM3, IDO, Adenosine receptor A2A, OX40, ICOS, M-CSF, IL2, IL7, and IL12. Moreover, the IES was exclusively correlated with the target genes of CEACAM, TGFB, and IL1. Conclusions: Expression levels of novel I-O target genes are correlated with three scores derived from AI-powered TIL analysis using H&amp;E slides, which can be easily applied to clinical research.[Table: see text]

Evolution of standard of care therapies used for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): A real-world analysis of patient health records from 2016 to 2019.

e18728 Background: The R/M HNSCC treatment landscape has evolved significantly in recent years, notably with the approval of 2 immuno-oncology agents (IO), pembrolizumab (second-line [2L] approval, 2016; first-line [1L] approval, 2019) and nivolumab (2L approval, 2016). Review of the literature suggests there is limited real-world (rw) data on clinical outcomes and safety associated with chemotherapy (chemo) and IO in R/M HNSCC. These analyses present a review of patient charts to assess rw clinical outcomes and safety in R/M HNSCC, stratified by patient factors. Methods: Data were derived via structured data extraction and manual review of electronic health records (EHRs; January 1, 2016–December 31, 2019) for patients with R/M HNSCC and who initiated systemic treatment at a community oncology practice in The US Oncology Network. Time-to-event endpoints were assessed by unadjusted Kaplan–Meier analyses and included death (rw overall survival [OS]), provider-assessed progression (rw progression-free survival [PFS]), rw duration of response (DoR), and treatment discontinuation (rw time-to-discontinuation [TTD]). Treatment sequences were evaluated following R/M HNSCC diagnosis. Provider-assessed response rates and adverse events (AEs) as captured in the EHRs were reported. Results: Overall, 257 patients who received 1L treatment were included in these analyses; median age was 64 years (range: 21, 90+); the majority of patients were male (77.4%) and white (74.7%), and 17.5% had evaluable PD-L1 status. The most common 1L treatment regimens were nivolumab (18.3%), carboplatin + paclitaxel (16.0%), and pembrolizumab (14.8%). Median follow-up time from treatment initiation was 7.9 months (range: 0.2, 45.9). Of the 174 patients with evaluable response to 1L treatment, overall response rate was 48.5% (95% CI: 38.3, 58.8) for chemo and 40.0% (95% CI: 28.9, 52.0) for IO. Median rwDoR was 7.6 months (95% CI: 5.8, 11.2). Median rwOS was 12.1 months (95% CI: 10.5, 16.6), and median rwPFS was 5.9 months (95% CI: 4.7, 6.8). Median rwTTD was 2.3 months (95% CI: 2.0, 3.2). The top reason for treatment discontinuation was treatment completion (38.5%) for chemo and progression (46.6.%) for IO. The most commonly reported AEs were rash (17.5%), fatigue (14.4%), and nausea (14.4%) for chemo and fatigue (12.4%), rash (7.2%), and anemia (5.2%) for IO. The percentage of AEs that did not require any intervention was 34.4% for chemo and 20.6% for IO. Conclusions: These analyses present rw clinical outcomes for patients with R/M HNSCC in community oncology practices. The proven role of IO continues to evolve, and continued work is needed to best demarcate the use of these agents, in addition to exploration of additional therapeutics for use in R/M HNSCC. Study funding: GlaxoSmithKline (GSK Study 207139).

Budget impact (BI) analysis of cemiplimab for first-line (1L) advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50% in the United States.

e18817 Background: Cemiplimab monotherapy (mono) demonstrated significant survival benefit versus chemotherapy (CT) in the first-line (1L) treatment of advanced NSCLC with PD-L1 ≥50%. This analysis estimated the BI of introducing cemiplimab in the US from the healthcare payer’s perspective, in the context of available treatments. Methods: Cohorts of patients (pts) with advanced NSCLC and PD-L1 ≥50% without EGFR/ ALK mutations were modeled over 3 years (yrs). Treatment duration inputs were based on median progression-free survival (PFS) from EMPOWER-Lung 1 trial for cemiplimab and CT, and published data on median PFS for other immuno-oncology (IO) agents. Market shares were based on market research and assumed the following distribution in the scenario without cemiplimab: 68% pembrolizumab (pembro); 15% pembro + CT; 6% durvalumab (durva); 4% platinum CT; 3% atezolizumab (atezo); 2% nivolumab (nivo); and 2% nivo + ipilimumab (ipi). Cemiplimab market share was assumed to increase from 1% (yr 1), to 6% (yr 2), to 10% (yr 3). The analysis assumed that 50% of the cemiplimab market share will come from displacement of pembro mono, whilst the other 50% will come from displacement of platinum CT, atezo, durva, nivo, and nivo + ipi. The market share for pembro + CT was assumed to remain the same in both scenarios. Monthly list price of cemiplimab was lower than pembro and nivo at the time of this research and were sourced from ProspectoRx drug pricing database. Adverse event costs were estimated using HCUP 2017 data and ICD-10 codes specific to each event and inflated to 2019 costs using medical inflation indices from Bureau of Labour Statistics. Disease management costs were per Centers for Medicare and Medicaid Services data. In univariate sensitivity analyses, inputs were varied by ±20% to model the impact on total incremental costs over 3 yrs. Results: In a hypothetical US healthcare plan of 1,000,000 members, ̃60 were eligible to receive 1L cemiplimab treatment for advanced NSCLC with PD-L1 ≥50% in yr 1. The average incremental cost per member per month was $0.0038. The 3-yr incremental cumulative BI of cemiplimab was $138,463, representing a 0.561% increase in the healthcare payer’s 3-yr expenditures on these 60 pts. The incremental cost of adding cemiplimab was $8,744 in yr 1; $50,187 in yr 2; and $79,533 in yr 3. The analysis was most sensitive to changes to the treatment duration for cemiplimab (±172%) and pembro (±93%). Changes to all other inputs had &lt; 20% impact. Conclusions: Cemiplimab is likely to be associated with a minimal increase in the budget for 1L treatment of advanced NSCLC with PD-L1 ≥50%. With a numerically lower list price relative to pembro and nivo, BI of cemiplimab was driven by the treatment duration for cemiplimab, which was higher than comparator treatments due to increased PFS.

Combination of immunotherapy and tyrosine kinase inhibitor in first-line metastatic renal cell carcinoma: A real-world Indian experience.

e16576 Background: Immuno-oncology (IO) agents in combination with oral tyrosine kinase inhibitors (TKIs) has become a standard first line therapy in metastatic renal cell carcinoma (mRCC) patients. Various combinations such as pembrolizumab + axitinib, avelumab + axitinib, nivolumab + cabozantinib and pembrolizumab + lenvatinib have all shown better results than sunitinib. There is very limited data about this from India. Methods: This is a single center, retrospective study of mRCC patients, who received first line treatment was nivolumab or pembrolizumab with axitinib or lenvatinib. The endpoints were objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AE). Results: Between Jan 2019 to Jan 2021, 22 patients were treated with IO + TKI combination. 12 patients received axitinib, and 10 lenvatinib. Age range was 35 to 78 years with 18 males and 4 females. IMDC risk stratification showed 3 favorable (13.6%), 13 intermediate (59%) and 6 poor risk (27.2%) patients. 2 patients (9%) achieved complete response(CR), 13 (59%) partial response (PR), 4 (18.2%) had stable disease and 3 (13.6%) progressed. The ORR was 68%. Median PFS was 22 months (1 month- 24 months). OS at 1 year was 92%, and median OS was not reached. Grade 3/4 immune related adverse events (AEs) were seen in 3 (14.2%) patients (1 colitis,1 pneumonitis,1 encephalitis), for whom the IO was discontinued. TKI related grade 3/4 AEs were seen in 8 patients (38%), and were managed with dose reductions. Conclusions: Combination IO + TKI is a very effective first line therapy in mRCC. An ORR of 68%, median PFS of 22 months and 1 year OS of 92% is the best we have seen in our patients. The efficacy of this combination is seen in all IMDC subgroups. The combination is well tolerated, and the TKI AEs are comfortably managed with dose reduction. IO combinations should be preferred over single agent TKIs (sunitinib or pazopanib) as first line therapy.

Increased neutrophil infiltration and lower prevalence of tumor mutation burden and microsatellite instability are hallmarks of RAS mutant colorectal cancers.

3563 Background: The tumor microenvironment (TME) of colorectal cancers (CRC) is modulated by oncogenic drivers such as KRAS. The TME comprises a broad landscape of immune infiltration. How tumor genomics associates with the immune cell landscape is less known. We aim to characterize immune cell types in RAS wild-type (WT) and mutant (MT) CRC, and to examine the prevalence of immuno-oncologic (IO) biomarkers (e.g. tumor mutation burden (TMB), PD-L1, MSI-H/dMMR) in these tumors. We performed genomic and transcriptomic analysis to confirm associations of mutant RAS with immune infiltration of the TME conducive to metastasis vs. potential response to immunotherapies. Methods: A total of 7,801 CRC were analyzed using next-generation sequencing on DNA (NextSeq, 592 Genes and WES, NovaSEQ), RNA (NovaSeq, whole transcriptome equencing) and IHC (Caris Life Sciences, Phoenix, AZ). MSI/MMR was tested by FA, IHC and NGS. TMB-H was based on a cut-off of &gt; 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Significance was determined by X2 and Fisher-Exact and p adjusted for multiple comparisons (q) was &lt;0.05. Results: Mutant KRAS was seen in 48% of mCRC tumors; NRAS in 3.7%, HRAS in 0.1%. The distribution was similar in patients &lt; or &gt;= than 50 yrs. In MSS tumors, there was a significantly higher neutrophil infiltration in KRAS MT (median cell fraction 6.6% vs. 5.9%) and NRAS MT (6.9%) overall and also when individual codons were studied. B cells, M2 macrophages, CD8+ T cells, dendritic cells and fibroblasts were lower in KRAS mutant tumors; B cells and M1 macrophages are lower in NRAS (q&lt;0.05). dMMR/MSI-H was significantly more prevalent in RAS WT (9.1%) than in KRAS (2.9%) or NRAS MT (1.8%) tumors, and highest in HRAS MT tumors (60%, q&lt;0.05).TMB-H was more prevalent in RAS WT (11%) than KRAS (5.8%) or NRAS (5.1%) MT, and highest in HRAS MT tumors (70%, all q&lt;0.05). In MSS tumors, KRAS MT tumors showed more TMB-H than WT (3.1% vs. 2.1%, q&lt;0.05), especially in KRAS non 12/13/61 mutations (5.5%, vs. 2.1%, q&lt;0.05) and G12C (4.4%, p&lt;0.05). PD-L1 expression was studied: in MSS tumors, KRAS-G12D (10.4%) and G13 MT (11.8%) showed higher mutation rates than RAS WT tumors (q&lt;0.05). Conclusions: KRAS &amp; NRAS mutations are associated with increased neutrophil abundance, with codon specific differences, while HRAS shows no difference. Overall CD8+ T cells and B cells are less abundant in KRAS &amp; NRAS mutants; substantial variability was seen amongst different protein changes. RAS mutations were more prevalent overall than generally reported, but did not vary by age. These results demonstrate significant differences in the TME of RAS mutant CRC that identify variable susceptibilities to immuno-oncologic agents, and provide further detailed characterization of heterogeneity between RAS variants, at the molecular as well as immunogenic levels.

U.S. budget impact analysis of biosimilar versus originator intravenous rituximab for the treatment of non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

e18820 Background: Rituximab-abbs is an anti-CD20 monoclonal antibody and an important immuno-oncology agent for the treatment of B-cell malignancies NHL (diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma [FL]) and CLL. It is also indicated for patients with RA, GPA, and MPA. Rituximab-abbs was the first rituximab biosimilar approved in the US and is expected to reduce drug acquisition costs. This budget impact model (BIM) estimated the impact of replacing a share of originator rituximab (IV-R-REF) use with rituximab-abbs (IV-R-BIOSIM) for NHL (DLBCL and FL), CLL, RA, GPA, and MPA. The objective was to project incremental annual cost differences between IV-R-BIOSIM and IV-R-REF for a hypothetical 1-million-member US healthcare insured (Medicare) population. Methods: An illustrative BIM estimated changes in 1-year drug and administration costs for an increased IV-R-BIOSIM uptake from 17.5% to 22.0%. Values for epidemiology, market share distribution, drug dosing, administration, and costs were derived from scientific literature, product labels, and publicly available cost resources. Dosing was based on a mean patient body surface area of 1.8 m2. Annual dose counts per patient were: 10 untreated FL with maintenance; 8 untreated FL (without maintenance), relapsed/refractory FL, or untreated DLBCL; 6 CLL, and 4 for RA, GPA, or MPA. All treatments were assumed to infuse over 3 hours. Drug acquisition and administration costs were from 2020 Average Sales Price pricing file and Centers for Medicare and Medicaid Services Physician Fee Schedule. Patient cost share was based on 2020 Medicare Part B 20% cost-share for office visits and drug products. Univariate sensitivity analyses were conducted. A scenario analysis was performed to project 2-year costs for extended FL maintenance treatment. Results: Estimated total annual plan incremental savings for a 1-million-member payer after the utilization shift were $312,379, equating to $0.31 per enrolled member per year (PMPY). Per-patient incremental drug cost savings with IV-R-BIOSIM for 1-year were $5,474–$12,924 (Table). The model was most sensitive to IV-R-REF cost and proportion of patients with RA. Conclusions: This analysis estimated annual savings of over $310,000 ($0.31 PMPY) for a 1-million-member US payer following a 4.5% utilization shift from IV-R-REF to IV-R-BIOSIM, demonstrating that IV-R-BIOSIM may confer considerable economic benefits vs originator rituximab.[Table: see text]

Testing of B7-H3 targeting antibody-drug conjugate (ADC) MGC018 in models of pediatric solid tumors by the Pediatric Preclinical Testing Consortium (PPTC).

10037 Background: B7-H3 (encoded by the CD276 gene) is an immunoregulatory molecule that is widely expressed in pediatric embryonal tumors and sarcomas, while expression is limited for normal tissues. Among PPTC models, osteosarcoma models showed highest CD276 transcript levels followed by Wilms tumor, neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma. Protein expression by IHC generally followed expression at the RNA level, with high expression by IHC observed across a range of models. MGC018 is a duocarmycin-based humanized ADC targeting B7-H3 that shows selective cytotoxicity for B7-H3 expressing cancer cells, robust in vivo activity against a range of adult cancer preclinical models, a favorable pharmacokinetic and safety profile in cynomolgus monkeys, and has entered clinical testing for adults with cancer. Herein we report the in vivo antitumor activity of MGC018 against preclinical models of pediatric solid tumors. Methods: MGC018 was tested at 6 mg/kg administered intraperitoneally (IP) on Day 1. SYD988, an anti-CD20 ADC with the same linker and payload as MGC018, was used as a control arm at 6 mg/kg IP on Day 1. Osteosarcoma models, due to their slower growth kinetics and lower rates of tumor regression, were tested with n = 10 mice per arm, while the sarcoma and neuroblastoma models were tested with n of 1 or n of 2 designs, respectively. Activity was evaluated using response criteria mirroring clinical criteria (progressive disease (PD), stable disease (SD), partial response (PR), complete response (CR), and maintained CR (MCR)], by minimum relative tumor volume across all models, and by event-free survival (EFS) comparisons between treatment groups. Results: For neuroblastoma models (n = 9), 3 and 2 neuroblastoma models showed objective responses (PR/CR/MCR) or SD, respectively, to MGC018, while none showed an objective response or SD to SYD988. For osteosarcoma, results are mature for 1 of 5 models, with this model showing an MCR response to MGC018 and a PD response to SYD988. For Ewing sarcoma (n = 5), a PR and MCR were observed to MGC018 with the remaining models showing PD; for SYD988 a single CR was observed with the remaining 4 models showing PD. For rhabdomyosarcoma (n = 3) 2 MCR and 1 PD were noted for MGC018, while only PD was noted for SYD988. EFS duration exceeding 100 days to a single dose of MGC018 was observed for 2 rhabdomyosarcoma, 1 Ewing sarcoma, and 1 neuroblastoma model. Evaluation of the relationship between B7-H3 expression and response to MGC018 will be performed when results from all studies are completed. Conclusions: B7-H3 is an important target for immuno-oncology agents for childhood cancers. Our results provide proof-of-principle for the ability of MGC018 to produce profound antitumor activity in select pediatric solid tumor models in a B7-H3 specific manner.

Cytokines in the Treatment of Melanoma.

The use of cytokines in harnessing the immune system to eradicate cancer has been an important treatment modality. However, the dose-limiting toxicities of these cytokines limited their usage in clinic. Here, we review the basic biology of cytokines involved in the treatment of melanoma and discuss their therapeutic applications. Moreover, we describe several innovative technological approaches that have been developed to improve the pharmacokinetics, safety, and efficacy of these cytokines. The safety and the anti-tumor activity of newly engineered cytokines including PEGylated IL-2 (NKTR-214), PEGylated IL-10 (AM0010), and IL-15 super agonist (ALT-803) have been evaluated in clinical trials with encouraging clinical activity and acceptable safety profile, both as single agents and in combination with immuno-oncology agents. A greater understanding of the mechanisms of action and effective dosing of these newly engineered cytokine together with determination of optimum combination therapy regimens may yield greater clinical benefits in the future.

Stay on Target: Reengaging Cancer Vaccines in Combination Immunotherapy.

Effective treatment of established tumors requires rational multicombination immunotherapy strategies designed to target all functions of the patient immune system and tumor immune microenvironment. While these combinations build on the foundation of successful immune checkpoint blockade antibodies, it is increasingly apparent that successful immunotherapy will also require a cancer vaccine backbone to engage the immune system, thereby ensuring that additional immuno-oncology agents will engage a tumor-specific immune response. This review summarizes ongoing clinical trials built upon the backbone of cancer vaccines and focusing on those clinical trials that utilize multicombination (3+) immuno-oncology agents. We examine combining cancer vaccines with multiple checkpoint blockade antibodies, novel multifunctional molecules, adoptive cell therapy and immune system agonists. These combinations and those yet to enter the clinic represent the future of cancer immunotherapy. With a cancer vaccine backbone, we are confident that current and coming generations of rationally designed multicombination immunotherapy can result in effective therapy of established tumors.

Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials

BackgroundImmuno-oncology (IO)–based therapies have been approved based on randomised clinical trials, yet a significant proportion of real-world patients are not represented in these trials. We sought to compare the outcomes of trial-ineligible vs. -eligible patients with advanced solid tumours treated with first-line (1L) IO therapy. Patients and methodsUsing the International Metastatic Renal Cell Carcinoma (RCC) Database Consortium and the Alberta Immunotherapy Database, patients with advanced RCC, non–small-cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition–based therapy were included. Trial eligibility was retrospectively determined as per commonly used exclusion criteria. The outcomes of interest were overall survival (OS), overall response rate (ORR), treatment duration (TD) and time to next treatment (TTNT). ResultsA total of 395 of 1241 (32%) patients were deemed trial-ineligible. The main reasons for ineligibility based on preselected exclusion criteria were Karnofsky performance status <70%/Eastern Cooperative Oncology Group performance status >1 (40%, 158 of 395), brain metastases (32%, 126 of 395), haemoglobin < 9 g/dL (16%, 63 of 395) and estimated glomerular filtration rate <40 mL/min (15%, 61 of 395).Between the ineligible vs. eligible groups, the median OS, ORR, median TD and median TTNT were 10.2 vs. 39.7 months (p < 0.01), 36% vs. 47% (p < 0.01), 2.7 vs. 6.9 months (p < 0.01) and 6.0 vs. 16.8 months (p < 0.01), respectively. Subgroup analyses showed statistically significant inferior OS, TD and TTNT for trial-ineligible vs. -eligible patients across all tumour types. Adjusted hazard ratios for death in RCC, NSCLC and melanoma were 1.84 (95% confidence interval [CI] 1.22–2.77), 2.21 (95% CI 1.58–3.11) and 1.82 (95% CI 1.21–2.74), respectively.. ConclusionsThirty-two percent of real-world patients treated with contemporary 1L IO-based therapies were ineligible for clinical trials. Although one-third of the trial-ineligible patients responded to treatment, the overall trial-ineligible population had inferior outcomes than trial-eligible patients. These data may guide patient counselling and temper expectations of benefit.

Adjuvant Systemic Therapy for High-risk Muscle-invasive Bladder Cancer After Radical Cystectomy: Current Options and Future Opportunities

We describe the case of a 71-yr-old woman with locally advanced muscle-invasive bladder cancer and stage III chronic kidney disease due to an obstructed nonfunctional left kidney. She was started on neoadjuvant immunotherapy, but had to stop treatment because of acute worsening of renal function. Radical cystectomy was then performed uneventfully, revealing pT3aN1 urothelial carcinoma of the bladder. Adjuvant chemotherapy in high-risk locally advanced bladder cancer after radical cystectomy currently poses several challenges, especially for cisplatin-ineligible candidates. Recent data on adjuvant immunotherapy trials suggest a disease-free survival advantage for this subgroup of patients. The current and future role of immuno-oncology agents in this setting is discussed. Patient summaryPatients with advanced bladder cancer might benefit from further chemotherapy or immunotherapy following bladder removal, but it is still unclear which patients benefit the most from this strategy. Measurement of biomarkers and scans to show urinary function will probably help in optimising patient selection for this treatment in the near future.