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Engineering immune cells to target cancer is a rapidly advancing technology. The first commercial products, chimeric-antigen receptor (CAR) T cells, are now approved for hematologic malignancies. However, solid tumors pose a greater challenge for cellular therapy, in part because suitable cancer-specific antigens are more difficult to identify and surrounding healthy tissues are harder to avoid. In addition, impaired trafficking of immune cells to solid tumors, the harsh immune-inhibitory microenvironment, and variable antigen density and presentation help tumors evade immune cells targeting cancer-specific antigens. To overcome these obstacles, T cells are being engineered to express defined T-cell receptors (TCR). Given that TCRs target intracellular peptides expressed on tumor MHC molecules, this provides an expanded pool of potential targetable tumor-specific antigens relative to the cell-surface antigens that are targeted by CAR T cells. The affinity of TCR T cells can be tuned to allow for better tumor recognition, even with varying levels of antigen presentation on the tumor and surrounding healthy tissue. Further enhancements to TCR T cells include improved platforms that enable more robust cell expansion and persistence; coadministration of small molecules that enhance tumor recognition and immune activation; and coexpression of cytokine-producing moieties, activating coreceptors, or mediators that relieve checkpoint blockade. Early-phase clinical trials pose logistical challenges involving production, large-scale manufacturing, and more. The challenges and obstacles to successful TCR T-cell therapy, and ways to overcome these and improve anticancer activity and efficacy, are discussed herein.

Purpose: As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically “cold” cancers, which are intrinsically insensitive to immunotherapy, as well as in “hot/warm” metastatic cancers that are, atypical of such cancers, resistant to immunotherapy. Patients and Methods: In a phase I, 3+3 dose-escalation trial (NCT03098160), evofosfamide (400–640 mg/m2) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1–2, while the latter was administered on day 8 of cycles 1–4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression. Results: Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer (n = 11), pancreatic cancer (n = 7), immunotherapy-resistant melanoma (n = 2), and human papillomavirus–negative head and neck cancer (n = 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m2 evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia. Conclusions: No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.

Background MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models. Methods Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel. Results ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent. Conclusion The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.

A major breakthrough in cancer treatment was ushered in by the development of immune checkpoint blockade therapy such as anti-CTLA4 antibody and anti-PD-1 and anti-programmed cell death-ligand 1 antibodies that are now approved for use in an increasing number of malignancies. Despite the relative success of immune checkpoint inhibitors with certain tumor types, many patients still fail to respond to such therapies, and the field is actively trying to understand the mechanisms of resistance, intrinsic or acquired, to immune checkpoint blockade. Herein, we discuss the roles that somatic genomic mutations in oncogenic pathways play in immune editing, as well as some of the current approaches toward improving response to immunotherapy.

Background Angiogenesis and activation of the epidermal growth factor (EGFR) pathway play an essential role in tumor proliferation and metastasis. Targeting angiogenesis or EGFR alone does not yield adequate tumor control in most solid tumors. Overcoming intrinsic and/or acquired resistance may need a doublet or triplet therapy strategy. Herein, we report the safety and feasibility of dual EGFR blockade with EGFR monoclonal antibody and EGFR tyrosine kinase inhibitor combined with anti-VEGF antibody in advanced solid tumors. Methods We conducted a phase I study combining erlotinib, cetuximab, and bevacizumab. Patients with advanced or metastatic solid tumors (excluding colorectal and non-small cell lung cancers) were analyzed for safety, toxicity profile, and response. Anti-tumor activity was evaluated per response evaluation criteria in solid tumors (RECIST 1.0). Results Thirty-six patients received treatment on a range of dose-levels. The most frequent tumor types enrolled were cervical (n = 10), head and neck squamous cell (n = 10), and follicular thyroid (n = 4) cancers. The most common treatment-related grade ≥ 2 adverse events were rash (56%), hypomagnesemia (17%), pruritus (11%), diarrhea (8%), and tumor-related bleeding (8%). Seventeen of 19 patients (89%) treated at the maximum tolerated dose did not present treatment-related dose-limiting toxicity. Fifteen (63%) of the 24 evaluable patients achieved a disease control (stable disease ≥ 4 months (n = 14) and partial response (n = 1). The median number of prior lines of therapies was 3 (range 1–10). Conclusions The triplet combination of erlotinib, cetuximab, and bevacizumab was well tolerated, conferring clinical benefit in heavily pretreated patients. Future studies are warranted with second or third-generation EGFR tyrosine kinase triplet combinations in the EGFR pathway aberrant patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00543504. Sponsor(s): National Cancer Institute (NCI), MD Anderson Cancer Center

Background: PTEN-deficient tumors are dependent on PI3Kβ activity, making PI3Kβ a compelling target. We evaluated the efficacy of PI3Kβ inhibitor AZD8186 on tumors with PTEN loss. Results: In vitro cell viability assay and immunoblotting demonstrated that PTEN loss was significantly correlated with AZD8186 sensitivity in triple negative breast cancer (TNBC) cell lines. Colony formation assay confirmed sensitivity of PTEN-deficient cell lines to AZD8186. AZD8186 inhibited PI3K signaling in PTEN loss TNBC cells. AZD8186 in combination with paclitaxel, eribulin had synergistic effects on growth inhibition in PTEN loss cells. AZD8186 promoted apoptosis in PTEN loss cells which was synergized by paclitaxel. In vivo, AZD8186 had limited activity as a single agent, but enhanced antitumor activity when combined with paclitaxel in MDA-MB-436 and MDA-MB-468 cell-line xenografts. AZD8186 significantly enhanced antitumor efficacy of anti-PD1 antibodies in the PTEN-deficient BP murine melanoma xenograft model, but not in the PTEN-wild-type CT26 xenograft model. Methods: In vitro, cell proliferation and colony formation assays were performed to determine cell sensitivity to AZD8186. Immunoblotting was performed to assess PTEN expression and PI3K signaling activity. FACS was performed to evaluate apoptosis. In vivo, antitumor efficacy of AZD8186 and its combinations were evaluated. Conclusions: AZD8186 has single agent efficacy in PTEN-deficient TNBC cell lines in vitro, but has limited single agent efficacy in vivo. However, AZD8186 has enhanced efficacy when combined with paclitaxel and anti-PD1 in vivo. Further study is needed to determine optimal combination therapies for PTEN-deficient solid tumors.

PURPOSE Human epidermal growth factor receptor 2 (HER2) is an effective therapeutic target in breast and gastric and gastroesophageal junction cancers. However, less is known about the prevalence of ERBB2 ( HER2) amplification and the efficacy of HER2-targeted treatment in other tumors. PATIENTS AND METHODS We assessed HER2 amplification status among 5,002 patients with advanced disease (excluding breast cancer) who underwent next-generation sequencing. We evaluated the clinical benefit of HER2-targeted therapy by measuring the time-dependent overall survival (OS) from the genomic testing results, progression-free survival (PFS), and PFS during HER2-targeted therapy (PFS2) compared with PFS during prior therapy (PFS1). RESULTS Overall, 122 patients (2.4%) had HER2 amplification, including patients with endometrial (5.3%), bladder (5.2%), biliary or gallbladder (4.9%), salivary (4.7%), and colorectal cancer (3.6%). Forty patients (38%) with nongastric, nongastroesophageal junction, or nonesophageal cancers received at least one line of HER2-targeted therapy. Patients receiving HER2-targeted therapy had a median OS of 18.6 months, compared with 10.9 months for patients who did not receive HER2-targeted therapy ( P = .070). On multivariable analysis, HER2-targeted therapy was significantly associated with increased OS (hazard ratio, 0.5; 95% CI, 0.27 to 0.93; P = .029), regardless of sex, age, or number of prior lines of treatment. The PFS2-to-PFS1 ratio was 1.3 or greater in 21 (57%) of 37 patients who received HER2-targeted therapy not in the first line of systemic treatment, and the median PFS2 and PFS1 times were 24 and 13 weeks, respectively ( P < .001). CONCLUSION HER2 amplifications using next-generation sequencing can be identified in a variety of tumor types. HER2-targeted therapy may confer clinical benefit in tumor types other than those for which HER2 inhibitors are approved.

Purpose Next-generation sequencing (NGS) for tumor molecular profiling can reveal secondary germline likely pathogenic and pathogenic variants (LPV/PV). The American College of Medical Genetics and Genomics (ACMG) recommends return of secondary results for a subset of 59 genes, but other genes with evidence of clinical utility are emerging. We previously reported that 4.3% of patients who underwent NGS of a targeted panel of 201 genes had LPV/PV on the basis of the ACMG list. We report the frequency of additional germline cancer-related gene variants and discuss their clinical utility. Patients and Methods Matched tumor and germline DNA NGS of a targeted panel of 201 genes was performed in a research laboratory on samples from 1,000 patients with advanced or metastatic solid tumors enrolled in a molecular testing protocol ( ClinicalTrials.gov identifier: NCT01772771). The frequency of germline LPV/PV in 54 cancer-related genes, beyond the genes in ACMG list, were analyzed. Results Among 1,000 patients who underwent tumor/normal DNA sequencing, 46 (4.6%) were found to have a germline LPV/PV in the following genes: AR (n = 5), ATM (n = 4), BAP1 (n = 1), CDH1 (n = 1), CDKN2A (n = 1), CHEK1 (n = 2), CHEK2 (n = 10), EGFR (n = 1), ERCC3 (n = 4), ERCC5 (n = 1), HNF1B (n = 1), HRAS (n = 1), MITF (n = 4), MLL3 (n = 1), NF1 (n = 3), PKHD1 (n = 4), PTCH1 (n = 1), and SMARCA4 (n = 1). Thus, 8.7% of patients had an LPV/PV, with two patients having two concomitant germline LPV/PV. Five mutations in high-penetrance hereditary cancer predisposition genes were selected to be returned to patients or their representatives: BAP1, CDH1, CDKN2A, EGFR, and SMARCA4. Conclusion Broader genomic testing is likely to identify additional secondary pathogenic germline alterations, some with potential clinical utility for return to patients and their relatives. The recommended genes for which germline results should be returned are continually changing, which warrants continued study.

Most tumors with activating MAPK (mitogen-activated protein kinase) pathway alterations respond poorly to MEK inhibitors alone. Here, we evaluated combination therapy with MEK inhibitor selumetinib and MDM2 inhibitor KRT-232 in TP53 wild-type and MAPK altered colon and thyroid cancer models. In vitro, we showed synergy between selumetinib and KRT-232 on cell proliferation and colony formation assays. Immunoblotting confirmed p53 upregulation and MEK pathway inhibition. The combination was tested in vivo in seven patient-derived xenograft (PDX) models (five colorectal carcinoma and two papillary thyroid carcinoma models) with different KRAS, BRAF, and NRAS mutations. Combination therapy significantly prolonged event-free survival compared with monotherapy in six of seven models tested. Reverse-phase protein arrays and immunohistochemistry, respectively, demonstrated upregulation of the p53 pathway and in two models cleaved caspase 3 with combination therapy. In summary, combined inhibition of MEK and MDM2 upregulated p53 expression, inhibited MAPK signaling and demonstrated greater antitumor efficacy than single drug therapy in both in vitro and in vivo settings. These findings support further clinical testing of the MEK/MDM2 inhibitor combination in tumors of epithelial origin with MAPK pathway alterations.

Background: Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) negatively regulates the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Triple negative breast cancers (TNBC) are often PTEN-deficient, making mTOR a compelling target. We evaluated the efficacy of catalytic mTOR inhibitor TAK228 alone and in combination with eribulin in TNBC. Results: Five of eight triple negative breast cell lines were sensitive to TAK228, independent of PIK3CA/PTEN status. Western blotting demonstrated inhibition of mTORC1/2 signaling as demonstrated by decreased phospho-AKT, phospho-S6 and phospho-4EBP1. In vitro, TAK228 was synergistic with eribulin in all eight TNBC cell lines. The combination of TAK228 and eribulin did not enhance apoptosis but increased G2/M growth arrest. In vivo, TAK228 led to modest growth inhibition in TNBC patient-derived xenografts (PDXs) with no tumor regression observed. In two TNBC PDXs with PTEN loss, one with intrinsic eribulin sensitivity, another eribulin resistance, TAK228 in combination with eribulin did not enhance in vivo efficacy. In a third PTEN-negative TNBC model, eribulin alone achieved disease stabilization, but the combination of TAK228 and eribulin led to significantly smaller tumor volumes compared to eribulin alone (p < 0.001). Methods: We tested in vitro efficacy of TAK228 in a panel of TNBC cell lines with cell proliferation assays. In vivo antitumor efficacy of TAK228 was evaluated alone and in combination with eribulin. Conclusion: TAK228 enhances the antitumor efficacy of eribulin in TNBC models in vitro, and enhanced in vivo activity in selected models. Further study is needed to determine the potential of this combination, and optimal patient selection strategies.

Background: PTEN functions as a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway to promote balanced cell proliferation, survival and differentiation. PTEN loss occurs across a variety of cancer subtypes; PTEN-deficient tumors are dependent on PI3Kβ activity, making PI3Kβ a compelling target. We evaluated the efficacy of PI3Kβ inhibitor AZD8186 as a single agent and in combination with standard chemotherapy and immune checkpoint inhibitors focused on tumors with loss of PTEN function. Methods: In vitro, cell proliferation assays were performed to determine the half maximal inhibitory concentration (IC50) after 3 days of treatment and to test the effects in combination with standard chemotherapy. Colony formation assays were performed to confirm efficacy of AZD8186 in PTEN-deficient cell lines. Western blot analysis was performed to assess PTEN protein expression and to evaluate effects of AZD8186 on PI3K signaling. In vivo, antitumor efficacy of AZD8186 as a single agent as well as in combination with paclitaxel and anti-PD1 was evaluated. Results: AZD8186 inhibited the cell proliferation of three of ten TNBC cell lines in vitro; PTEN loss was significantly correlated with AZD8186 sensitivity (p= 0.008). Colony formation assay confirmed sensitivity of PTEN-deficient cell lines to AZD8186. AZD8186 inhibited PI3K signaling with decreased expression of pAKT, pGSK3β, pPRAS40 and pS6. AZD8186 treatment of PTEN-deficient cell lines, MDA-MB-436 and MDA-MB-468, resulted in increased apoptosis. Cell proliferation assays demonstrated additive effect of the combination of paclitaxel with AZD8186. AZD8186 significantly enhanced antitumor activity of paclitaxel in MDA-MB-436 and MDA-MB-468 cell-line-derived xenografts, with disease stabilization in the latter. In syngeneic models, AZD8186 enhanced antitumor efficacy of anti-PD1 antibodies in PTEN-deficient BP murine melanoma xenograft (p=0.0073), but not in PTEN-wildtype colon carcinoma, CT26. Conclusion: AZD8186 has single agent efficacy in PTEN-deficient triple negative breast cancer cell lines in vitro, with modest single agent efficacy in vivo. AZD8186 enhanced the antitumor efficacy of paclitaxel and of Anti-PD1 antibodies in vivo. Further study is needed to determine optimal combination therapies for PTEN-deficient solid tumors. Citation Format: Owusu-Brackett N, Zhao M, Akcakanat A, Evans KW, Yuca E, Tapia C, Ileana-Dumbrava E, Janku F, Meric-Bernstam F. Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss [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 P6-21-04.

Purpose: TROP2 is overexpressed in many tumor types and is being actively pursued as a target. Sacituzumab govitecan (SG), a humanized anti-TROP2 antibody conjugated with SN-38, was approved for treatment of metastatic triple negative breast cancer, with the greatest efficacy in patients with medium or high TROP2 levels. We sought to enhance efficacy of TROP2-targeted therapies by pharmacological regulation of TROP2 expression. Methods: TROP2 levels were assessed by immunohistochemistry (IHC) in two sets of breast tumors: a set of surgical samples and a tissue microarray. TROP2 mRNA expression was assessed in surgical samples and breast cancer patient-derived xenografts (PDXs) with RNAseq and assessed in the TCGA. In cell lines, expression of TROP2, E-cadherin (E-cad), and Schlafen family member 11 (SLFN11) were assessed by immunoblotting and qPCR following drug treatment or cell line manipulation. Epithelial-mesenchymal transition was evaluated by cell migration, cell invasion, and anchorage-independent growth assays. Antitumor efficacy of drug combination was assessed by cell survival, cell colony formation, and apoptosis assays. Results: By IHC, TROP2 was expressed in only 40% of metaplastic breast cancers (MpBC), but nearly all non-MpBC tumors. TCGA database evaluation further showed higher TROP2 levels in non-MpBC tumors than metaplastic tumors. In breast cancer surgical specimens, breast cancer PDXs, and the TCGA, there was a strong correlation between TROP2 and E-cad expression. In vitro, we demonstrated that downregulating transcriptional factor zinc finger E-box binding homeobox 1 (ZEB1) led to mesenchymal-epithelial transition with upregulation of both E-cad and TROP2 expression in breast cancer cells, leading to increased sensitivity to SG treatment. Screening of epigenetic modulators identified DNA methyltransferase inhibitor decitabine as an enhancer of TROP2 and E-cad expression in PDX cell lines of metaplastic cancer origin and mesenchymal subtype breast cancer cell lines. Decitabine increased TROP2 expression by decreasing TROP2 promoter methylation. Decitabine was significantly synergistic with SG, and enhanced apoptosis. Similarly, overexpression of TROP2 (by plasmid) in cell lines enhanced activity of SG. Furthermore, decitabine increased expression of SLFN11, a putative biomarker of SN38 sensitivity, and was synergistic with SG in TROP2 expressing, SLFN11 low breast cancer cell lines. Conclusion: TROP2 is expressed in most breast cancers, but is expressed less frequently in MpBC, an aggressive subtype unresponsive to traditional therapies. Epigenetic modulator decitabine upregulates TROP2 and SLFN11 expression and enhances antitumor efficacy of SG. Combinatorial treatment of TROP2 ADCs with epigenetic modulators of TROP2 represent a novel therapeutic strategy for tumors with low TROP2 or SLFN11 expression. Citation Format: Ming Zhao, Timothy P. DiPeri, Gabriela Raso, Yasmeen Q. Rizvi, Xiaofeng Zheng, Kurt Evans, Argun Akcakanat, Fei Yang, Debu Tripathy, Ecaterina Ileana Dumbrava, Senthil Damodaran, Funda Meric-Bernstam. Epigenetically upregulating TROP2 enhances therapeutic efficacy of TROP2 ADC sacitizumab govitecan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1791.

DNA polymerase proofreading and mismatch repair deficiency have different microsatellites signatures.

Background ADP-A2M10 SPEAR T-cells are genetically engineered autologous T-cells that express a high affinity MAGE-A10-specific T-cell receptor targeting MAGE-A10+tumors in the context of HLA A*02. This trial is no longer enrolling (NCT02989064). Methods This ADP-A2M10 dose escalation trial utilized a modified 3+3 design to evaluate safety and antitumor activity. Patients (pts) with advanced head and neck squamous cell carcinoma (HNSCC), melanoma, or urothelial cancer (UC) were enrolled. Pts were HLA A*02+ with tumors expressing MAGE A10. Pts underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the MAGE-A10 TCR, and expanded. Eligible pts underwent lymphodepletion with fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 was administered at Dose Level (DL) 1 = 0.1 × 109, DL2 = >1.2 - 6×109, and Expansion = 1.2–15×109 transduced cells. Results As of January 10, 2020, 10 pts (8 male and 2 female) with HNSCC (4), melanoma (3), and UC (3) cancers were treated. Three pts each were treated at DL1 and DL2 and 4 pts were treated in Expansion. The most frequently reported adverse events ≥ Grade 3 were lymphopenia (10 pts), neutropenia (10), anemia (8), leukopenia (7), and thrombocytopenia (5). Two pts reported CRS (1 Grade 1, 1 Grade 3) with resolution. Responses included: 3 pts - stable disease, 5 pts – progressive disease, 1 pt – not evaluable, and 1 pt too early to determine. ADP-A2M10 SPEAR T-cells were detectable in peripheral blood from pts at each dose level and in tumor tissues from several pts at Expansion. Conclusions There was no evidence of on- or off-target toxicity. Given the minimal antitumor activity and the discovery that MAGE-A10 expression frequently overlaps with MAGE-A4 expression, the clinical program has closed. Several trials with SPEAR T-cells targeting MAGE-A4 are ongoing (https://bit.ly/35htsZK). Trial Registration NCT02989064 Ethics Approval The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.

Osimertinib improves disease-free survival for patients with early stage EGFR -mutated non-small cell lung cancer after complete tumor resection.

IntroductionImmunotherapies have revolutionized the treatment of various cancers, but little is known about their symptomatic toxicity. Assessing these symptoms is best accomplished by asking the patients themselves. However, such reports are subjective and may face challenges as bonafide scientific data. Demonstrating the validity of symptom assessment tools, mainly through the reduction of measurement errors, has the potential to improve patient care if these tools are widely adopted. To that end, we present herein the psychometric properties of the Immunotherapy for Early-Phase Trials module of the MD Anderson Symptom Inventory (MDASI-Immunotherapy EPT) in patients receiving various immunotherapies in early phase trials at a major cancer center.MethodsOne hundred forty-five patients completed the inventory at baseline, with 85 of them also doing so after 9 weeks of treatment. The mean (±SD) age of the patients was 57.0±12.9 years. Also, 56% of the patients were women, 79% identified as white, and 49% had at least some college education.ResultsThe internal consistency reliability of the MDASI-Immunotherapy EPT was excellent, as the Cronbach’s alphas for all of its subscales were at least 0.88 (range 0.88–0.95). Known-group validity based on Eastern Cooperative Oncology Group performance status groupings was excellent at 9 weeks after the start of an immunotherapy trial for the MDASI-Immunotherapy EPT severity (effect size, 0.96) and interference (effect size, 0.82) subscales. We found substantial changes in the symptom items difficulty remembering (effect size, −0.85), fever and/or chills (effect size, −0.63), disturbed sleep (effect size, −0.52), diarrhea (effect size, −0.42), and swelling of hands, legs, or feet (effect size, −0.39).ConclusionsIn conclusion, the MDASI-Immunotherapy EPT is a valid, reliable, and sensitive tool for measuring symptomatic toxicity.

Combination of a PARP inhibitor with immune checkpoint blockade showed promising antitumor activity without additional toxicity.

PD-L1 blockage on dendritic cells, but not macrophages, may enhance antitumor or CD8 + T cell responses leading to greater tumor growth inhibition.

Patients with cancer are more vulnerable to COVID-19 infection with higher risk of severe symptoms and death.

Pembrolizumab combined with neoadjuvant chemotherapy improves therapeutic responses in patients with early triple-negative breast cancer.

Activation of the fibroblast growth factor receptor (FGFR) signaling pathway is commonly involved in carcinogenesis,1 and oncogenic molecular alterations in the FGFR pathway occur across various tumor types.2 Agents that target FGFR have been demonstrated to inhibit tumor growth and angiogenesis—and, in some cases, to reverse acquired resistance to anticancer agents—in patients with FGFR alterations in urothelial carcinoma,3,4 cholangiocarcinoma,5 glioblastoma,6 and non–small-cell lung cancer (NSCLC).7 Here, we present the first report, to our knowledge, of a patient with head and neck squamous cell carcinoma (HNSCC) with FGF amplifications who achieved a complete response to an FGFR inhibitor.

BackgroundCOM701, a novel first-in-class immune checkpoint inhibitor (ICI) binds to poliovirus receptor related immunoglobulin domain containing (PVRIG) leading to enhanced activation of T and NK-cells. COM701 in combination with nivolumab has a favorable safety profile, is well tolerated and demonstrates antitumor activity.1 We hypothesized that the addition of BMS-986207 as a triplet thereby inhibiting the DNAM axis will have an acceptable safety/tolerability profile. We present preliminary results on safety/tolerability and pharmacokinetics (PK) parameters.MethodsUsing an accelerated titration and 3+3 study design we enrolled 14 patients (pts) with advanced solid tumors. Doses of COM701 were 0.3, 1, 3, 10 or 20 [mg/kg IV Q4 wks]; in combination with nivolumab and BMS-986207 (both 480 mg IV Q4 wks). Key objectives were to evaluate the safety and tolerability, to determine the recommended dose for expansion (RDFE) and to characterize preliminary pharmacokinetic parameters. Key inclusion criteria: Age ≥ 18 yrs, histologically confirmed locally advanced or metastatic solid malignancy and has exhausted all available standard treatments. Key exclusion criteria: history of immune-related toxicities on prior immunotherapy treatment leading to discontinuation.ResultsIn the safety population [N=14], 12 pts reported treatment emergent adverse events (TEAEs). The most frequent TEAES [≥3 pts] were fatigue 5 pts (36%), pyrexia 3 pts (21%), vomiting 3 pts (21%). No DLTs were reported in any of the dose levels. The most frequent tumor types enrolled: CRC (n=3), and prostate, melanoma and OVCA/primary peritoneal cancer (n=2 each). Median number of prior therapies was 10 (range 1–19). Four pts had received prior immunotherapy. Serious adverse events [≥2 pts] were 2 pts (14%) with G3 abdominal pain, 2 pts (14%) with vomiting (1pt with G1/2 vomiting, 1 pt with G3 vomiting) all assessed by the investigator as unrelated to study drug. Preliminary PK profiles of COM701 were generally dose proportional.ConclusionsCOM701 in combination with BMS-986207 and nivolumab demonstrates a favorable safety, tolerability and PK profiles. COM701 20 mg/kg has been selected as the RDFE in combination with BMS-986207 and nivolumab (both 480 mg) all administered IV Q4 wks. The expansion cohorts are enrolling pts with platinum resistant ovarian cancer and endometrial cancer. Data cutoff 28 Jun 2021.AcknowledgementsThis study is in collaboration with Bristol Myers Squibb.Trial RegistrationNCT04570839ReferencesVaena, DA, Fleming GF et al. COM701 with or without nivolumab: Results of an ongoing phase 1 study of safety, tolerability and preliminary antitumor activity in patients with advanced solid malignancies (NCT03667716). J Clin Oncol 2021;39: (suppl 15; abstr 2504).Ethics ApprovalThe study obtained ethics approval form all the participating sites. All study participants gave informed consent before taking part.- 0002: START2020.15- 0003: 20210109- 0005: IRB20-1549- 0006: 21-060- 0007: IRB-AAAT4904- 0012: 2020-0755- 0013: STMW2020.16- 0015: 20210109

BackgroundT-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory domains (TIGIT), and costimulatory receptor CD226 competitively bind 2 ligands, CD155 and CD112, which are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment.1 2 Dual TIGIT/programmed cell death protein-1 (PD-1) blockade increased tumor antigen-specific CD8+ T-cell expansion and function in vitro and promoted potent antitumor response in vivo.3 4 TIGIT/PD-1 dual blockade using a TIGIT monoclonal antibody (mAb) with intact Fc produced clinical responses in advanced cancer.5 SEA-TGT is an investigational, human, nonfucosylated mAb directed against TIGIT. SEA-TGT binds to TIGIT, blocking inhibitory checkpoint signals directed at T cells. SEA-TGT enhances binding to activating FcγRIIIa and decreases binding to inhibitory FcγRIIb; this depletes immunosuppressive regulatory T cells and amplifies naive and memory T cells, potentially augmenting PD-1 inhibition effects. Preclinically, at suboptimal doses, SEA-TGT plus anti-PD-1 mAbs had superior antitumor activity than either agent alone.6MethodsSafety and antitumor activity of SEA TGT in ~377 adults (≥18 years) will be evaluated in this phase 1, multicenter, open-label, dose-escalation/expansion study. Part A will assess the safety/tolerability of SEA TGT to determine maximum tolerated and recommended doses. Part B will assess the safety and antitumor activity of the recommended dose in disease-specific expansion cohorts. Part C will assess SEA-TGT plus sasanlimab in dose-expansion cohorts after an initial safety run-in. Patients with histologically/cytologically confirmed relapsed/refractory/progressive metastatic solid tumors including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), gastric/gastroesophageal junction carcinoma, cutaneous melanoma, bladder, cervical, ovarian or triple-negative breast cancer, or selected lymphomas will be eligible for Parts A and B. Part C will enroll patients with histologically confirmed advanced NSCLC (high [tumor proportion score (TPS) ≥50%] and low [TPS=1–49%] PD ligand 1 [PD-L1] expression), cutaneous melanoma, and HNSCC without previous anti–PD-1/PD-L1 therapy exposure. SEA TGT will be administered on Day 1 of 21-day cycles.Laboratory abnormalities, adverse events, dose-limiting toxicities, and dose-level safety and activity are primary endpoints. Secondary endpoints are objective response (OR) and complete response (CR) rates, duration of OR/CR, progression-free survival, overall survival, pharmacokinetics (PK), and antidrug antibodies. Exploratory analysis will include pharmacodynamics (PD), PK/PD relationships, biomarkers, and resistance to SEA-TGT. This trial is recruiting in Europe and North America.Trial RegistrationNCT04254107ReferencesBlake SJ, Dougall WC, Miles JJ, et al. Molecular pathways: Targeting CD96 and TIGIT for cancer immunotherapy. Clin Cancer Res 2016;22(21):5183–5188.Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J ImmunoTher Cancer 2020;8:e000957.Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 2014;26(6):923–937.Chauvin JM, Pagliano O, Fourcade J, et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest 2015;125(5):2046–2058.Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase 2 study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol 2020;38(15 suppl):9503.Smith A, Zeng W, Lucas S, et al. Poster 1583. SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents. Presented at: American Association for Cancer Research Annual Meeting; April 9–14, 2021; Virtual Meeting.Ethics ApprovalInstitutional review boards or independent ethics committees of participating sites approved the trial, which will be conducted in compliance with the Declaration of Helsinki and International Conference on Harmonisation Guidelines for Good Clinical Practice. All patients will provide written informed consent.

BackgroundCOM902 is an IgG4 fully human high-affinity monoclonal antibody, inhibitor of TIGIT (T cell Ig and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain) binding to poliovirus receptor (PVR). TIGIT blockade by COM902 was shown to enhance anti-tumor immunity in pre-clinical models. We hypothesized that COM902 as monotherapy will have an acceptable safety and tolerability profile in subjects with advanced solid tumors.MethodsUtilizing an accelerated titration and 3+3 study design we enrolled 18 patients (pts) at the following COM902 doses 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 mg/kg IV Q3 wks. Key primary objectives were to evaluate the safety, tolerability (CTCAE v5.0), to characterize the pharmacokinetics (PK) and to select a recommended dose for expansion (RDFE). An exploratory objective was evaluation of peripheral receptor occupancy (RO). Key inclusion criteria: Age ≥18 yrs, histologically/cytologically confirmed advanced malignancy who have exhausted all available standard therapy or not a candidate for standard therapy. Patients with performance status ECOG 0-1, prior ICI permissible. Dose-limiting toxicities (DLTs) were evaluated within a 21-day window in the 1st cycle of dose escalation.ResultsIn the safety population [N=18], 12 pts reported treatment emergent adverse events (TEAEs). The most frequent TEAES [≥2pts] were fatigue 7 pts (39%) all G1/2, diarrhea 3 pts (17%) all G1/2. Two pts reported DLTs deemed related to study drug, a pt with G2 nausea (single pt cohort, 0.01 mg/kg) and a pt with G3 atrial fibrillation (1 mg/kg). Serious adverse events were reported in 2 pts, 1 pt with atrial fibrillation (deemed by the investigator as possibly related to COM902) and 1 pt with spinal cord compression (deemed by the investigator as unrelated to COM902, related to disease). Preliminary PK profiles were generally dose proportional and peripheral RO above 90% was reported from 0.1 mg/kg dose.ConclusionsCOM902 has an acceptable safety, tolerability and PK profiles. A COM902 3 mg/kg IV Q3 wks is the RDFE. Enrollment into combination cohort (COM902 + COM701), for evaluation of safety/tolerability at the RDFE of both study drugs, combination dose expansion (COM902 + COM701) in pts with HNSCC, NSCLC and CRC-MSS and COM902 monotherapy dose expansion (pts with multiple myeloma) all at the RDFE of study drug(s) are planned. Data cut June 28, 2021.Trial RegistrationNCT04354246Ethics ApprovalThe study obtained approval from IRBs of the participating clinical trial sites. The study participants gave informed consent before taking part.o 0002: MOD01006350 (START)o 0003: 20202320 (West Cancer Center)o 0012: 2020–0195 (MDACC)o 0013: MOD01006350 (START midwest)o 0014: 20202320 (OSU)

Background: To date, anti-HER2 monoclonal antibodies are the only immune therapies approved for treating pts with HER2-over-expressing cancers. Intratumoral delivery of immunostimulatory adjuncts such as toll-like receptor (TLR) 7/8 agonists can activate tumor resident antigen-presenting cells (APCs) to promote antitumor immunity. To optimize intratumoral delivery while leveraging favorable preclinical biology we developed a novel, systemically delivered ISAC (BDC-1001). BDC-1001 consists of an investigational trastuzumab biosimilar chemically conjugated to a TLR 7/8 agonist (payload) with an intervening non-cleavable linker. BDC-1001 activates human myeloid APCs and retains antibody-mediated effector functions such as antibody-dependent cellular cytotoxicity/phagocytosis. Our trastuzumab-based ISACs seem to elicit potent and durable immune-mediated antitumor efficacy including tumor regression in a TLR- and Fc receptor-dependent manner in xenograft and syngeneic tumor resistant models (Ackerman et al. Nat Cancer 2020). BDC-1001 did not induce interstitial lung disease, cytokine release syndrome, or thrombocytopenia in non-human primate studies. A four-part phase 1/2, first-in-human study was initiated in 2020 to evaluate BDC-1001 with or without (±) pembro in pts with HER2-overexpressing or amplified advanced solid tumors. Methods: This phase 1/2 dose-escalation/expansion study will enroll up to 390 pts with HER2-overexpressing (IHC2+ or 3+) or HER2-amplified (by in situ hybridization or next-generation sequencing) advanced solid tumors. Patients may have received prior anti-HER2 therapies. Primary objectives of dose-escalation are safety and tolerability, and establishing a recommended phase 2 dose of BDC-1001 alone administered IV q3w (Part 1) and combined with pembro (Part 2). Primary endpoints of Parts 1 & 2 include assessment of safety and tolerability; dose-limiting immune-related toxicities in a 3+3 design. The dose-expansion phase 2 portion will evaluate preliminary antitumor activity of BDC-1001 alone (Part 3) and with pembro (Part 4) using RECIST v1.1 and iRECIST. The primary endpoint of the phase 2 is best\ overall response rate; with secondary endpoints of duration of response, disease control rate, and progression-free survival. Exploratory objectives include pharmacokinetic parameters and pharmacodynamic biomarkers associated with drug exposure to help elucidate mechanism of action and identify biomarkers to improve selection of pts most likely to benefit from the single therapy or combination. Recruitment is ongoing (NCT04278144). Citation Format: Manish R. Sharma, Richard D. Carvajal, Daniel Catenacci, Leisha A. Emens, Glenn J. Hanna, Dejan Juric, Yoon-Koo Kang, Jeeyun Lee, Keun-Wook Lee, Bob T. Li, Kathleen Moore, Mark D. Pegram, Paula R. Pohlmann, Drew Rasco, Alexander Spira, Arielle L. Heeke, Ding Wang, Lawrence Garbo, Sudhir Manda, Jasgit Sachdev, Shelley E. Ackerman, Heidi LeBlanc, David Dornan, Marcin Kowanetz, Michael N. Alonso, Amreen Husain, Edith A. Perez, Ecaterina Ileana Dumbrava. Phase 1/2 study of a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), BDC-1001, alone and in combination with pembrolizumab (pembro) in patients (pts) with HER2-expressing advanced solid tumors [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 CT218.

Background: Wee1 kinase, which prevents premature mitotic entry by inhibiting cyclin-dependent kinases (CDKs), may be essential when cyclin E1 is overexpressed in order to prevent DNA damage and cell death. In preclinical studies, cancer models harboring CCNE1 amplification are highly sensitive to treatment with adavosertib, a Wee1 kinase inhibitor. A multicenter phase 2 study was conducted to assess the antitumor activity of adavosertib in patients with CCNE1 amplified advanced refractory solid tumors. Methods: Patients with advanced refractory solid tumors harboring CCNE1 amplification pre-identified in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. They had refractory disease, on standard options available, or they declined standard-of-care therapy. Eligible patients must be aged ≥ 18 years and had measurable disease per RECIST (Response Evaluation Criteria in Solid Tumors) 1.1, ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, and adequate organ functions. After informed consent, patients received adavosertib 300 mg daily on days 1 to 5 and 8 to 12 of a 21-day cycle. The primary endpoint was objective response rate (ORR). The trial employed Simon's two-stage design. Results: Between January 22, 2019 and May 20, 2020, 29 patients with 12 tumor types were enrolled on study: ovarian = 14, breast = 3, endometrial = 2; and carcinosarcoma, cholangiocarcinoma, esophageal, gallbladder, germ cell tumor, melanoma, prostate, sarcoma, sarcomatoid and urothelial = 10 (1 each tumor). Median follow-up was 11.7 months. The median line of prior systemic therapy was 4 (range 1-8). Twenty-seven patients were evaluable for response. In these patients, 7 confirmed partial responses (PR) were observed, for an ORR of 25.9% (95% CI 15.1-47.5%). The median progression-free survival was 4.0 months and one-year overall survival was 55%. In 13 patients with measurable high-grade serous ovarian cancer, 5 achieved PR (38.5%) and 8 had stable disease ≥6 months/PR (61.5%). Other PRs were seen in 1 urothelial carcinoma and 1 melanoma. Fifteen patients experienced grade 3 or higher treatment-related adverse events: neutropenia (24%), thrombocytopenia (17%), anemia (14%), nausea (17%), diarrhea (17%) and fatigue (17%). Sixteen patients required dose duction of adavosertib to 250 mg, and 7 further to 200 mg. Biomarker analysis is ongoing to investigate potential biomarkers of response. Conclusions: Adavosertib monotherapy demonstrates promising clinical activity in patients with refractory solid tumors harboring CCNE1 amplification, especially in high-grade serous ovarian cancer. Further exploration of adavosertib in CCNE1 amplified high grade serous ovarian cancer is warranted. Citation Format: Siqing Fu, Shuyang Yao, Yuan Yuan, Rebecca A. Previs, Anthony D. Elias, Richard Carvajal, Thomas J. George, Ying Yuan, Yuko Yamamura, Shannon Westin, Yan Xing, Ecaterina E. Ileana Dumbrava, Daniel D. Karp, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Jordi Rodon, Naoko Takebe, Charles Kunos, Karen Lu, Khanda Keyomarsi, Funda Meric-Bernstam. Phase II trial of the Wee1 inhibitor adavosertib in advanced refractory solid tumors with CCNE1 amplification [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 974.

Background: Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) negatively regulates the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Triple-negative breast cancers (TNBC) are often PTEN-deficient, making mTOR a compelling target. We evaluated the efficacy of catalytic mTOR inhibitor TAK228 alone and in combination with eribulin in TNBC. Methods: We tested TAK228 in combination with eribulin in a panel of TNBC cell lines with cell proliferation assays. Western blot analysis was performed to assess PTEN status and PI3K pathway inhibition. In vivo, antitumor efficacy of TAK228 as a single agent as well as in combination with eribulin was evaluated. Results: Five of eight triple-negative breast cell lines were sensitive to TAK228, independent of PIK3CA/PTEN status. Western blotting demonstrated inhibition of mTORC1/2 signaling as demonstrated by decreased phospho-AKT, phospho-S6 and phospho-4EBP1. In vitro, TAK228 was synergistic with eribulin in all eight TNBC cell lines. The combination of TAK228 and eribulin did not enhance apoptosis but increased G2/M growth arrest (p Conclusion: TAK228 enhanced the antitumor efficacy of eribulin in TNBC models in vitro and enhanced in vivo activity in selected models. Further study is needed to determine the potential of this combination and optimal patient selection strategies. Citation Format: Nicci Owusu-Brackett, Kurt W. Evans, Argun Akcakanat, Erkan Yuca, Ecaterina Ileana Dumbrava, Filip Janku, Funda Meric-Bernstam. TAK228 enhances antitumor activity of eribulin in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B07.

Background: Cell-free DNA (cfDNA) analysis from plasma offers a minimally invasive detection of genomic alterations in personalized cancer therapy. PIK3CA is an actionable gene, which can be targeted with PI3K, AKT and mTOR inhibitors. We hypothesized that common hot-spot PIK3CA mutations can be detected in small amount of plasma cfDNA from patients with progressing advanced cancers. Methods: PIK3CA mutations (p.H1047R, p.H1047L, p.E542K and p.E545K) were detected by droplet digital PCR (QX 200, BioRad) using 16 ng of unamplified cfDNA from plasma of 68 patients with advanced cancer. Results were compared to the clinical molecular testing of archival tumor tissue performed by next-generation sequencing or PCR during the clinical care. Results: Of 68 patients (breast cancer, n=41; colorectal cancer, n=13; other tumor types, n=14), 58 patients (85%) had a PIK3CA mutation in the tumor. Testing of plasma cfDNA was in agreement with tumor tissue in 72% of samples (kappa 0.38), sensitivity 67% and specificity 100%. Of 19 falsely negative plasma cfDNA samples, 6 were found to be collected from patients not having disease progression. Additional 9 samples with available cfDNA were retested with increased DNA input (22-247 ng) and 4 had a PIK3CA mutation resulting in agreement for patients with progressing cancers of 85% (kappa 0.61), sensitivity 83% and specificity 100%. Patients with plasma PIK3CA-mutant cfDNA variant-allele frequency (VAF) < 8.5% ( Conclusion: Common PIK3CA mutations can be detected in plasma cfDNA with high sensitivity and specificity in patients with progressing cancer if the cfDNA input is sufficient. Low amount of PIK3CA-mutant cfDNA is associated with longer survival. Changes in PIK3CA VAF could be an early surrogate biomarker for time to treatment failure to PI3K-targeted therapies. This abstract is also being presented as Poster B16. Citation Format: Ecaterina E. Ileana Dumbrava, Helen J. Huang, Ana Stuckett, Kiran Madwani, Abha Adat, David S. Hong, Sarina A. Piha-Paul, Vivek Subbiah, Daniel D. Karp, Siqing Fu, Aung Naing, Apostolia M. Tsimberidou, Stacey Moulder, Kimberly Koenig, Carlos H. Barcenas, Bryan Kee, David Fogelman, Scott Kopetz, Funda Meric-Bernstam, Filip Janku. PIK3CA mutations in plasma cell-free DNA predict survival and treatment outcomes in patients with advanced cancers [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr PR10.

Background: TT-00420, a multikinase inhibitor, targets cell proliferation, angiogenesis, and immunomodulatory pathways by inhibiting the mitotic kinases Aurora A/B, Janus kinases (JAK) involved in cytokine signalling, and receptor tyrosine kinases involved in angiogenesis (FGFRs and VEGFRs). These pathways are important in the pathogenesis of triple negative breast cancer (TNBC) and TT-00420 has shown preclinical efficacy against multiple subtypes of TNBC. Methods: This phase I, open-label, first-in-human study is enrolling adult patients with advanced or metastatic TNBC and other advanced solid tumors. The study contains a dose escalation phase (N=22), followed by dose expansion in two parallel cohorts, a TNBC cohort (N=22) and a selected advanced tumor (SAT) cohort (N=22). The provisional dose range for dose escalation is 1 mg/d to 20 mg/d. Dose escalation is guided by Bayesian modeling with overdose control until a dose recommended for dose expansion is determined. Adverse events (AE) are evaluated per CTCAE v5.0 criteria, and tumor response is evaluated per RECIST v1.1 criteria. Patients receive a single daily oral administration of TT-00420 continuously for 28-day cycles. The primary endpoint is to evaluate dose limiting toxicity (DLT) and identify a maximum tolerated dose (MTD). Secondary objectives include evaluating the efficacy and pharmacokinetic profile of TT-00420. Results: As of the data cut-off date on September 26, 2019, 11 patients have received TT-00420 treatment in 4 dose levels, 1 mg/d (N=1), 3 mg/d (N=1), 5 mg/d (N=3), and 8 mg/d (N=6). No DLTs have been observed at any of the tested dose levels. Commonly reported suspected AEs across all tested dose levels were grades 1 or 2 diarrhea (n=4, 36.4%), myalgia (n=2, 18.2%) and hypertension (n=2, 18.2%). Two suspected serious adverse events reported were grade 2 hypertension (8 mg/d) and grade 3 nausea (5 mg/d). No grade 3 AEs have occurred in more than one subject. Stable disease has been observed in 4 patients, including a metastatic TNBC patient treated at 8 mg/d, who received 9 lines of prior antineoplastic therapy. Per RECIST v1.1 criteria, this TNBC patient had a 21% decrease in target lesions observed on restaging after two cycles of TT-00420 treatment. Interestingly, significant clinical improvement in the skin lesions were observed as well. More detailed data from this TNBC patient and other patients treated in the study will be presented. Enrollment in dose escalation is currently ongoing. Clinical trial information: NCT03654547 Citation Format: Sarina A. Piha-Paul, Ecaterina Ileana-Dumbrava, Filip Janku, Daniel D. Karp, Funda Meric-Bernstam, Jordi Rodon, Brenda Ngo, Peng Peng, Frank Wu. Phase I study of TT-00420, a multiple kinase inhibitor, in patients with triple negative breast cancers and other advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3011.

Introduction: COM701 is a novel first-in-class Immune checkpoint inhibitor (ICI) that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG) blocking its interaction with its ligand, PVRL2 and regulating the activity of T/NK cells through the DNAM/TIGIT axis. In preclinical experiments inhibition of PVRIG alone and in combination with anti-PD1 and/or TIGIT leads to tumor growth inhibition and activation of T-cells in the microenvironment generating an antitumor response. Methods: A total of 28 pts (Arm A/B 16/12) with a variety of cancer types were enrolled. Hybrid accelerated (1st 4 dose cohorts in Arm A) and 3+3 study design (cohorts 5-8 in Arm A and all cohorts in Arm B). Patients with performance status ECOG 0-1 and advanced or metastatic solid tumors who failed standard of care tx were eligible. Prior ICIs were permissible. In Arm A pts received COM701 monotherapy 0.01, 0.03, 0.1, 0.3, 1, 3, 10mg/kg (all IV Q 3 weeks (wks)) and 20 mg/kg (IV Q 4 wks). In Arm B, pts received COM701 at 0.3, 1 or 3mg/kg plus nivolumab 360mg IV q3 wks (3 pts/dose cohort) and 3 pts received 10mg/kg plus nivolumab 480mg IV q4 wks. Treatment emergent adverse events (TEAEs) were reported per CTCAE v4.03 and responses per RECIST v1.1. Dose-limiting toxicities (DLTs) were evaluated within a 21-day or 28-day window (for 3- or 4-wks dosing schedule respectively). Data cutoff date was January 23, 2020. Results: The median number of prior anticancer therapies were: Arm A, 7 (range 2-15), Arm B, 5 (range 2-9). No DLTs have been reported in any of the dose cohorts. Tx was well tolerated with no subjects discontinuing tx due to toxicity, the most frequent TEAEs in Arm A were fatigue (46%), nausea (31%) and anxiety (23%) - all G1-2. In Arm B ≥4 pts - anemia, lower extremity edema, rash and fatigue the majority being grade 1-2 (88%). In Arms A+B: partial response (PR) + stable disease (SD) was 57% (16/28). Of note: Arm A (COM701 20mg/kg IV q4 wks): confirmed PR in a pt with primary peritoneal cancer ongoing on tx > 15 weeks. Arm B: unconfirmed PR in a pt with MSS-CRC on COM701 0.3mg/kg plus nivolumab 360mg IV q3 wks, ongoing on tx >34 wks). Overall 11/28 pts remain on study tx including 3 pts who have not reached 1st imaging assessment. Conclusion: COM701 is well tolerated as monotherapy and in combination with nivolumab in a variety of heavily pretreated pts with advanced or metastatic solid tumors. COM701 demonstrates encouraging preliminary antitumor activity with objective responses as monotherapy and in combination with nivolumab in hard to treat tumor types (primary peritoneal and MSS-CRC). Citation Format: Ryan Sullivan, Drew Rasco, Emerson Lim, Manish Sharma, Dale Shepard, Amita Patnaik, Erika Hamilton, Gini Fleming, Kyri Papadopoulos, Adam ElNaggar, Adeboye Henry Adewoye, Bartosz Chmielowski, Ecaterina Dumbrava, Dan Vaena. COM701 demonstrates preliminary antitumor activity as monotherapy and in combination with nivolumab in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT031.

Background: Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have rapidly become a pivotal approach to cancer therapy. Nivolumab is an anti-PD1 antibody approved for treatment of melanoma, lung, renal cell, head and neck squamous, urothelial and increasing number of other solid and hematological malignancies. However, patients with history of autoimmune disorders are excluded from the majority of clinical trials testing ICI. Consequently, the risks of flare ups and worsening of pre-existing autoimmune disorders in patients with tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to patients with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis and others autoimmune disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in patients with autoimmune diseases and advanced or metastatic solid tumors. The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in patients with autoimmune disorders and advanced or metastatic solid tumors. Secondary objectives are to evaluate the antitumor efficacy, the impact of nivolumab on the autoimmune disease severity indices, and to explore potential biomarkers of response, resistance or toxicity. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced or metastatic solid tumors in which ICI are approved or have shown clinical activity, Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Key overall exclusion criteria include prior therapy with an anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 patients will be included in each disease cohort at each severity level. Primary endpoints are dose-limiting toxicities defined for each autoimmune disease-specific cohort, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response, progression free and overall survival and cohort specific tumor tissue, blood and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is currently enrolling patients in the participating sites through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03816345. Citation Format: Ecaterina E. Ileana Dumbrava, Maria Suarez-Almazor, Jeane Painter, Tanner M. Johanns, Michael L. Dougan, Laura Cappelli, Yinghong Wang, Clifton Bingham, Sarthak Gupta, Blake M. Warner, Osama Rahma, Jarushka Naidoo, Patrick A. Ott, David A. Hafler, Harriet Kluger, Arezou Khosroshahi, Rafeh Naqash, Lorinda Chung, Tamiko R. Katsumoto, Shivaani Kummar, Hussein Tawbi, Elad Sharon. A phase 1b study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT249.

12044 Background: While safety and dose-finding remain the primary objective of Phase 1 trials, the potential for clinical benefit has taken a greater meaning in the last decade with the novel therapies. With data from phase I trials being submitted for regulatory approval, the finer details of these studies are under even more scrutiny: in particular, do the trial participants reflect the general patient population for whom the drug may be indicated? To that end, we investigated age-based enrollment on phase I clinical trials over time. Methods: We queried a prospectively maintained database at a major phase I trials center to identify eligible patients and demographic + clinical variables including phase I trial characteristics, age at date of enrollment into 3 age-based cohorts: AYA ages 15-39y, mid-age 40-64y, older adults aged 65y+. We calculated descriptive statistics, and explored correlations (Pearson/Spearman) and associations (linear regression) between age and independent variables. Results: Over a 3-year period (1/1/17 to 12/31/19), we identified 6267 pts enrolled on 338 phase I trials. Median overall age 58.4y (range 15.5-95.1y). 729 (12%, median age 34.8y) were AYA, 3652 (58%, median age 55.4y) mid-age and 1886 (30%, median 70y) older adults, of whom 870 pts were aged 70-79y and 76 pts aged 80y+ (18 being >85y). There was no association b/w senior participation and year of enrollment (2017 31%, 2018 29%, 2019 30%, b/w age and type of therapy (i.e. targeted vs immunotherapy, etc.) or b/w age and # of drugs given on trial (single agent vs combo) (all p > 0.05). Conclusions: Older adults remain underrepresented on phase I trials esp. when compared to incidence of cancer in that age group (30% enrollment vs 60% incidence), a discordance more staggering in the oldest old pts (85y+; only 18 pts enrolled over 3 yrs when compared to 140,690 pts 85y+ w a new cancer dx in just 2019). Once enrolled, older adults received similar types of phase I therapies with comparable number of drugs as compared to middle age patients, i.e. older adults were just as likely to get immunotherapy or targeted therapy as well mono- vs combo therapy as mid-age pts. [Table: see text]

TPS3158 Background: Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have become a pivotal approach to cancer therapy. Nivolumab is an anti-PD1 antibody approved for an increasing number of solid tumors and hematological malignancies. However, patients (pts) with history of autoimmune disorders are excluded from the majority of clinical trials testing ICI. Consequently, the risks of flares and worsening of pre-existing autoimmune disorders in pts with tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to pts with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis, Sjögren's Syndrome and Other Autoimmune Disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in pts with autoimmune diseases and advanced malignancies (NCT03816345). The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in pts with autoimmune disorders and advanced malignancies. Secondary objectives are to evaluate the antitumor efficacy, the impact of nivolumab on the autoimmune disease severity indices, and to explore potential biomarkers of response, resistance or toxicity. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced malignancies in which ICI are approved or have shown clinical activity. Key overall exclusion criteria include prior therapy with anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 pts will be included in each disease cohort at each severity level. Primary endpoints are dose-limiting toxicities, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response, progression free and overall survival and cohort specific tumor tissue, blood and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is enrolling pts through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03816345 .

3629 Background: ATM is frequently mutated in cancer, and defects may serve as a putative predictive biomarker. However, the functional impact of most ATM variants is not well known. In this study, we examined the relationship between ATM variants and ATM protein expression to better discern ATM functional defects in patients (pts) with advanced cancer. Methods: We retrospectively identified pts seen at MD Anderson Cancer Center who had ATM variants detected on CLIA-certified next generation sequencing (NGS) assays. ATM immunohistochemistry (IHC) was performed on available tumors. We then prospectively assessed ATM IHC on tumors from pts who were referred for DNA damage repair inhibitor (DDRi) trials. Functional classification of the variants was performed via published in silico tools and/or precision oncology decision support (PODS). An IHC cut-off of 100% loss in tumor cell nuclei defined ATM loss of protein (LOP). Results: Of 1394 ATM-mutant tumors identified retrospectively, ATM alterations were classified as 16% (N = 216) inactivating, 12% (N = 163) potentially inactivating, 71% (N = 993) variant of unknown significance (VUS), and 2% (N = 22) benign. Coding variants were seen across the ATM exonic structure/splice sites, and 20 individual variants were shared in > 10 pts. 263/297 available retrospective tumor samples had interpretable IHC results; 27% (N = 72) had ATM LOP. LOP was most prevalent in tumors with inactivating ATM variants (39/100, 39%); but, importantly, LOP was seen in 20% (N = 33/162) of potentially inactivating/VUS, thus better clarifying their functional impact. In the prospective cohort of 217 pt tumors, 17% (N = 37) had ATM LOP. 29% (N = 62/217) of this cohort also had ATM variants. ATM LOP was seen in 48% of tumors with inactivating variants (N = 14/29), 25% of tumors with potentially/VUS(N = 9/36), and 9% (N = 14/156) of tumors without ATM variants identified. ATM LOP was detected most commonly in colorectal (24%; N = 8/34), cholangiocarcinoma (20%; N = 6/30), prostate (16%; N = 16/104) and pancreatic (9%; N = 1/11) cancers among this cohort of pts referred for DDRi trials. Conclusions: ATM coding variants occurred across the gene, with certain variants shared across tumor types. The functional impact of most ATM variants was VUS, and ATM LOP can help clarify function in up to 25% of these VUS. Also, ATM LOP can be seen even in tumors without ATM variants identified, suggesting epigenetic or post-translational loss. Future prospective studies assessing predictive capability of paired DNA and protein-level profiling of ATM are warranted.

BackgroundPatients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers.MethodsIn this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR).ResultsA total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma–pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug.ConclusionsThe favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma–pheochromocytoma supports further evaluation of pembrolizumab in this patient population.Trial registration numberNCT02721732

TPS23 Background: COM701 is a novel 1st-in-class monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG) blocking its interaction with its ligand, PVRL2. In preclinical experiments inhibition of PVRIG alone and in combination with a PD-1 inhibitor leads to activation of T cells in the tumor microenvironment generating an anti-tumor immune response leading to tumor growth inhibition. Novel checkpoint therapies are needed for the treatment of patients with advanced malignancies. We hypothesized that COM701 monotherapy and in combination with nivolumab will be safe and tolerable and demonstrate preliminary antitumor activity in pts with advanced solid malignancies. Methods: This ongoing phase 1 study (NCT03667716) is evaluating the safety and tolerability of escalating doses of COM701 monotherapy IV Q3 or Q4 weekly and in combination with nivolumab 360 mg IV Q3 weekly or 480 mg IV Q4 weekly. Key Inclusion Criteria: Age ≥18 yrs, histologically or cytologically confirmed advanced solid malignancy and has exhausted all available standard therapy, ECOG performance status 0-1, prior ICI permissible. Key Exclusion Criteria: Symptomatic interstitial lung disease or inflammatory pneumonitis, untreated or symptomatic central nervous system metastases. Primary outcome measures are the incidence of adverse events and dose-limiting toxicities (21-day or 28-day DLT window), pharmacokinetics of COM701 and to identify the maximum tolerated dose and/or the recommended dose for expansion. Key secondary outcome measures are to characterize the immunogenicity and preliminary antitumor activity of COM701 as monotherapy and in combination with nivolumab. Study Design: Hybrid accelerated titration and 3+3 study design. Statistical Considerations: Adverse events graded as per CTCAE v4.03, responses as per RECIST v1.1. Analyses of all study objectives are descriptive and hypothesis generating. As of the date of this submission dose level 8 of COM701 monotherapy and dose level 3 of the combination arm are open to enrollment. Updated data will be presented at the conference. Clinical trial information: NCT03667716.

Background: The PI3K pathway is frequently dysregulated in cancer, promoting tumorigenesis by facilitating aberrant cell growth, blocking apoptotic signaling, and suppressing immune surveillance in the tumor microenvironment (TME). The TME contains regulatory immune cells such as FOXP3+ regulatory T cells (Tregs), myeloid-derived suppressor cells, M2 macrophages, and N2 neutrophils, maintaining an immunologically isolating sheath. PI3K inhibition has been shown to slow tumor growth by inducing apoptosis and sensitizing tumors to T cell-mediated cytotoxicity. Copanlisib is a potent PI3K inhibitor, and combination with the PD-1 checkpoint inhibitor nivolumab is hypothesized to result in robust anti-tumor T cell responses. Materials and Methods: Open label phase I trial of copanlisib and nivolumab following a 3+3 design with an expansion phase at the maximally tolerated dose (MTD). Flat-dose nivolumab is administered intravenously (IV) on day 1 while copanlisib is administered IV weekly on days 1, 8 and 15 of a 28-day cycle; there is a 2-week copanlisib run-in during cycle 1 (expansion phase) to enable assessment of pharmacodynamic (PD) endpoints. Prior checkpoint inhibitor therapy is not permitted. Dose-limiting toxicities (DLTs) were assessed during cycle 1, and responses are assessed by CT using RECIST 1.1 and iRECIST. Exploratory PD objectives include assessments on blood and tissue samples collected at baseline and post copanlisib -/+ nivolumab treatment; these studies will evaluate immune cell populations, PD-1/PD-L1 levels, markers of T cell activation/inhibition (Zap70 pY493 and SHP2 pY542), and apoptosis biomarkers using validated immunofluorescence and flow cytometry assays. Results: As of July 2019, 16 pts have been enrolled with 6 pts in the expansion phase; 14 pts are evaluable for toxicity. The MTD for the combination is copanlisib 60 mg days 1, 8 and 15 plus nivolumab 480 mg day 1 (recommended doses for each individual agent, 28-day cycles); no DLTs were identified. Median age on study is 62 (range 38-77). One pt (rectal cancer) has experienced a confirmed partial response (PR), and 4 pts have achieved stable disease (SD; 1 pt remains on study ≥10 months). Five pts are too early to assess for response. Tissue for molecular analysis and/or genomic sequencing has been collected for all patients. Adverse events include: grade 3 hypertension (1 pt, requiring dose reduction) and infusion-related reaction (hypertension, 1pt); grade 1/2 events include hypertension (7 pts), hyperglycemia (5 pts), nausea (5 pts) and infusion-related reaction (hypertension, 4 pts). Preliminary PD assessments show increases in the number of CD8+ T cells in peripheral blood samples after treatment, with changes in phospho-biomarkers of T cell activation (Zap70-pY493 and SHP-pY542). Conclusions: The combination is tolerable using the approved doses of each individual agent and shows treatment-induced immune PD changes as well as early anti-tumor activity. Enrollment at the expansion stage is ongoing (NCT03502733). Funded by NCI Contract No. HHSN261200800001E. Citation Format: Geraldine O'Sullivan Coyne, Timothy A Yap, Nancy Moore, Arjun Mittra, Naoko Takebe, Lamin Juwara, Sabrina Khan, Ecaterina Ileana Dumbrava, Howard Streicher, Richard Piekarz, Elad Sharon, Funda Meric-Bernstam, Ralph Parchment, Tony Navas, King Leung Fung, James Mitchell, Kristin Fino, Sandra Montez, Austin Doyle, Laurence Rubinstein, James H Doroshow, Alice P Chen. Phase IB combination study of copanlisib and nivolumab in advanced solid tumors and lymphomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B105. doi:10.1158/1535-7163.TARG-19-B105

Immune checkpoint inhibitors such as anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), anti PD-1 (programmed cell death protein 1) and PD-L1 (programmed cell death protein-ligand 1) monoclonal antibodies are emerging as standard oncology treatments in various tumor types. The indications will expand as immunotherapies are being investigated in various tumors with promising results. Currently, there is inadequate identification of predictive biomarkers of response or toxicity. Unique response patterns include pseudoprogression and delayed response. The use of immune checkpoint inhibitors exhibit an unique toxicity profile, the immune-related adverse events (irAEs). The most notable immune reactions are noted in skin (rash), gastrointestinal track (colitis, hepatitis, pancreatitis), lung (pneumonitis), heart (myocarditis), and endocrine system (thyroiditis, hypophysitis). We present a patient with metastatic adenoid cystic carcinoma of the left submandibular gland with granulomatous inflammation of the lacrimal glands and axonal neuritis of the cervical and paraspinal nerves following treatment with ipilimumab and radiation therapy.

Next-generation sequencing (NGS), also known as massively parallel sequencing, is rapidly being incorporated into oncology practice. Interpretation of genomic reports and selecting treatments based on the tumor's genomic analysis becomes more and more complicated for the treating oncologist because of the use of larger panels covering dozens to hundreds of genes and the amount of rapidly emerging clinical/translational data. To help guide personalized treatments in oncology, The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT) at MD Anderson Cancer Center has developed a knowledge base, available at https://personalizedcancertherapy.org or https://pct.mdanderson.org (PCT). This knowledge base provides information on the function of common genomic alterations and their therapeutic implications. Here, we describe how such genomic information can be used by health-care providers to identify genomically matched therapies.

With the increasing availability of genomics, routine analysis of advanced cancers is now feasible. Treatment selection is frequently guided by the molecular characteristics of a patient's tumor, and an increasing number of trials are genomically selected. Furthermore, multiple studies have demonstrated the benefit of therapies that are chosen based upon the molecular profile of a tumor. However, the rapid evolution of genomic testing platforms and emergence of new technologies make interpreting molecular testing reports more challenging. More sophisticated precision oncology decision support services are essential. This review outlines existing tools available for health care providers and precision oncology teams and highlights strategies for optimizing decision support. Specific attention is given to the assays currently available for molecular testing, as well as considerations for interpreting alteration information. This article also discusses strategies for identifying and matching patients to clinical trials, current challenges, and proposals for future development of precision oncology decision support. Clin Cancer Res; 24(12); 2719–31. ©2018 AACR.

BACKGROUND: ~30% cancer patients develop brain metastases (BM), reflected by ~1600 BM patients treated at MD Anderson Cancer Center annually. With advances in systemic therapy and extracranial disease control, BM is a growing challenge. Multi-disciplinary BM management is critical and complex requiring coordination of multiple oncology sub-specialties. There is limited data on pragmatic clinic models to streamline and advance care. METHODS: Recognizing deficiency in BM treatment and research, a steering committee was formed at MDACC to establish an interdisciplinary BM clinic (BMC), with a multi-disciplinary BM research retreat held in 2016. The goal of BMC was to centralize patient referrals, improve patient outcomes and experience, and advance research by developing clinical trials and biomarker discovery programs. Meetings were held to address BMC format, workflow, EMR integration, data collection infrastructure, and staffing model. RESULTS: MDACC BMC clinic opened in 01/2019 with two half-day clinics staffed by neurosurgery, neuro-radiation oncology, neuro-radiology and medical/neuro oncology. A dedicated advanced practice provider screens the referrals according to a well-developed algorithm. A multidisciplinary conference is held immediately before each clinic where patient images are reviewed, cases are discussed and consensus recommendations are developed. The treatment plan and follow up appointments are arranged at the completion of the clinic visit to expedite care. ~50 patients have been seen with excellent patient satisfaction response and reduced time to treatment. ~20% patients had major change in treatment plan following multi-disciplinary evaluation. Additional efforts to develop a central BM database along with clinical and translational research programs are on-going. CONCLUSIONS: Establishment of a multi-disciplinary BMC to facilitate care and centralize research programs addresses a critical need for coordinated patient-centered BM management. This endeavor has enhanced patient experience through multi-specialty collaboration. Our program demonstrates the feasibility and effectiveness of a dedicated BMC in the treatment of this complex patient population.

3014 Background: A subset of tumors possess genetic or microenvironmental alterations that render cells dependent on mitochondria oxidative phosphorylation (OXPHOS) for survival. IACS, a potent oral selective inhibitor of mitochondrial complex I, showed robust responses in multiple preclinical tumor models, providing strong rationale for clinical testing. Methods: Pts with advanced cancers received IACS in increasing dose levels (DL) using 3+3 dose escalation. 7-day QD induction of IACS was followed by maintenance weekly (QW) or twice weekly (BIW) dosing. Phamacokinetics (PK), lactate and pH were assessed serially. Paired tumor biopsies were assessed for pharmacodynamic and predictive biomarkers. Results: 18 pts were treated; M/F 16/2; ECOG PS 0/1: 3/15. Mean age 49 (23-69) yrs. Tumors comprised advanced colorectal (n = 4), castration resistant prostate cancer (CRPC) (n = 3), pancreatic (n = 2), other cancers (n = 9). DL1: 2mg QD 7 days induction/0.5mg QW maintenance (n = 3); DL2: 2.5mg QD 7 days/1mg QW (n = 3); DL3: 3mg QD 7 days/3mg QW (n = 3); DL4: 2.5mg QD 7 days/2.5mg BIW (n = 4); DL5: 2mg QD 7 days/2mg BIW (n = 5). IACS was well tolerated with 12 (67%) pts reporting G1-2 IACS related toxicities, such as raised lactate (n = 10), nausea (n = 8), fatigue (n = 7), vomiting (n = 5), myalgia (n = 4) and peripheral neuropathy (n = 4). 1 pt in DL3 and 2 pts in DL4 had ≥G3 IACS related toxicities, such as nausea (n = 2), vomiting (n = 1), raised lactate (n = 1), dehydration (n = 1), visual changes (n = 1), and peripheral neuropathy (n = 1). Raised lactate was not associated with acidosis. DL5 is now being expanded to assess the maximum tolerated dose (MTD). PK showed good oral bioavailability, with long T1/2 and low intrapatient variability. Cmax = 14nM on Day 7 at the end of DL5 induction phase, confirming biologically active doses. 7 pts had best response of RECIST stable disease. A pt with heavily pretreated CRPC achieved RECIST partial response with resolution of CRPC related pain. Conclusions: IACS is well tolerated with preliminary evidence of antitumor activity. MTD expansions include CRPC, TNBC, pancreatic cancer and molecularly selected (ENO1 loss; SMARCA4 mutation) tumor cohorts. Clinical trial information: NCT03291938.