Modest Improvement In Overall Survival Research Articles

Combination of dual JAK/HDAC inhibitor with regorafenib synergistically reduces tumor growth, metastasis, and regorafenib-induced toxicity in colorectal cancer

BackgroundTreatment with regorafenib, a multiple-kinase inhibitor, to manage metastatic colorectal cancers (mCRCs) shows a modest improvement in overall survival but is associated with severe toxicities. Thus, to reduce regorafenib-induced toxicity, we used regorafenib at low concentration along with a dual JAK/HDAC small-molecule inhibitor (JAK/HDACi) to leverage the advantages of both JAK and HDAC inhibition to enhance antitumor activity. The therapeutic efficacy and safety of the combination treatment was evaluated with CRC models.MethodsThe cytotoxicity of JAK/HDACi, regorafenib, and their combination were tested with normal colonic and CRC cells exhibiting various genetic backgrounds. Kinomic, ATAC-seq, RNA-seq, cell cycle, and apoptosis analyses were performed to evaluate the cellular functions/molecular alterations affected by the combination. Efficacy of the combination was assessed using patient-derived xenograft (PDX) and experimental metastasis models of CRC. To evaluate the interplay between tumor, its microenvironment, and modulation of immune response, MC38 syngeneic mice were utilized.ResultsThe combination therapy decreased cell viability; phosphorylation of JAKs, STAT3, EGFR, and other key kinases; and inhibited deacetylation of histone H3K9, H4K8, and alpha tubulin proteins. It induced cell cycle arrest at G0-G1 phase and apoptosis of CRC cells. Whole transcriptomic analysis showed that combination treatment modulated molecules involved in apoptosis, extracellular matrix-receptor interaction, and focal adhesion pathways. It synergistically reduces PDX tumor growth and experimental metastasis, and, in a syngeneic mouse model, the treatment enhances the antitumor immune response as evidenced by higher infiltration of CD45 and cytotoxic cells. Pharmacokinetic studies showed that combination increased the bioavailability of regorafenib.ConclusionsThe combination treatment was more effective than with regorafenib or JAK/HDACi alone, and had minimal toxicity. A clinical trial to evaluate this combination for treatment of mCRCs is warranted.

Abstract 585: Regorafenib antitumor immune response is enhanced by a novel drug combination in CRC syngeneic model

Abstract Purpose: In the United States, colorectal cancer (CRC) is the second leading cause of cancer mortality. Metastatic CRC (mCRC) refractory to traditional chemotherapy is managed with regorafenib, a multiple-kinase inhibitor. However, patients show only a modest improvement in overall survival but experience high drug toxicity, adverse side effects, and poor tolerability. Thus, to reduce regorafenib-induced toxicity and to enhance antitumor activity, we combined it with a hybrid/dual JAK/HDAC small-molecule inhibitor (JAK/HDACi) to leverage the advantages of both JAK and HDAC inhibition in a single agent. With syngeneic mice, the efficacy and impact on immunomodulation of this drug combination was assessed. Methods: To assess effects of the agents, C57BL/6 immunocompetent mice were injected with MC38 murine CRC cells and treated with regorafenib (6mg/kg body wt) or JAK/HDACi (30mg/kg body wt), and their combination every third day for 21 days. Upon completion of the experiment, the tumors were harvested and processed for RNA and protein expression profiles. The effect of drug treatment on immune response was analyzed by nCounter Gene Expression assays (NanoString Technologies). Cytokines were measured in serum using the MesoScale Discovery mouse V-Plex Proinflammatory Panel kit. For pharmacokinetic studies, plasma samples were assayed from C57BL/6 treated with drugs after 1, 7, 21, and 48 hrs of treatment. Results: The combination treatment significantly reduced tumor growth (volume and weight),relative to the vehicle control or single treatments. Gene expression showed higher CD45 abundance score in the combination treatment. This is an exciting observation, as CD45 has phosphatase activity and dephosphorylates key targets of the drugs used in the study. Additionally, after treatment with the combination, there was higher expression of Gzmb and Gzme and lower expression of Cx3cr1, indicating enhanced immuno modulation relative to regorafenib alone. We confirmed these findings by immunoprofiling of tumors. Higher CD45 staining, noted in tumors of mice treated with the combination, corroborated the gene expression results. Pronounced CD8 T lymphocytes infiltration was observed in combination, compared to regorafenib alone. Reduction of proinflammatory cytokine, TNF-α was noted in the combination group. This is an interesting observation as CD45 negatively regulates TNF, and combination treated mice had highest number of CD45 positive cells. Pharmacokinetic studies showed that the bioavailability of regorafenib was elevated after combination treatment relative to single-agent treatment. Conclusions: Relative to the single agents, the combination of regorafenib with JAK/HDACi was more effective, with an elevated antitumor immune response and with sustained inhibition of tumor growth. A clinical trial to evaluate this combination for the treatment of mCRCs is warranted. Citation Format: Prachi Bajpai, Farrukh Afaq, Sameer Al Diffalha, Sumit Agarwal, Hyung Gyoon Kim, Dennis Otali, Sooryanarayana Varambally, Ashish Manne, Ravi Paluri, Moh’d Khushman, Upender Manne. Regorafenib antitumor immune response is enhanced by a novel drug combination in CRC syngeneic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 585.

Current and Emerging Therapeutic Targets for the Treatment of Cholangiocarcinoma: An Updated Review.

Cholangiocarcinoma is a malignancy of the bile ducts that is often associated with late diagnosis, poor overall survival, and limited treatment options. The standard of care therapy for cholangiocarcinoma has been cytotoxic chemotherapy with modest improvements in overall survival with the addition of immune checkpoint inhibitors. The discovery of actionable mutations has led to the advent of targeted therapies against FGFR and IDH-1, which has expanded the treatment landscape for this patient population. Significant efforts have been made in the pre-clinical space to explore novel immunotherapeutic approaches, as well as antibody-drug conjugates. This review provides an overview of the current landscape of treatment options, as well as promising future therapeutic targets.

New Opportunities to Individualize Frontline Therapy in Advanced Stages of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally and is rising in incidence. Until recently, treatment options for patients with advanced stages of HCC have been limited to antiangiogenic therapies with modest improvements in overall survival. The emerging role of immunotherapy with immune checkpoint inhibitors (ICI) in oncology has led to a rapid expansion in treatment options and improvements in outcomes for patients with advanced stages of HCC. Recent clinical trials have shown meaningful survival improvement in patients treated with the combination of bevacizumab and atezolizumab, as well as with the combination of tremelimumab with durvalumab, resulting in regulatory approvals of these regimens as frontline therapy. Beyond improvements in overall survival, ICI-based combination regimens achieve higher rates of durable treatment response than multikinase inhibitors and have favorable side effect profiles. With the emergence of doublet anti-angiogenic and immune checkpoint inhibitor (ICI) and dual ICI combinations, individualized therapy is now possible for patients based on co-morbidity profiles and other factors. These more potent systemic therapies are also being tested in earlier stages of disease and in combination with loco-regional therapies such as trans-arterial chemoembolization and stereotactic body radiotherapy. We summarize these advances and emerging therapeutic combinations currently in clinical trials.

A phase 1b, open-label, two-part safety, tolerability, and efficacy study of a soluble beta-glucan (odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma whose disease did not progress during first-line (1L) chemotherapy.

TPS4201 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease with a 5-year overall survival (OS) rate of 3%. Standard of care treatment is continuous cytotoxic chemotherapy which produces modest improvements in OS but is also associated with significant toxicity raising the need for novel treatment paradigms. Although immunotherapy has yet to produce clinical benefit for most patients with PDAC, preclinical modeling demonstrates its potential and show that combinations of myeloid agonists can trigger robust synergistic anti-tumor activity against PDAC tumors that are otherwise resistant to immunotherapy including immune checkpoint blockade (anti-CTLA4, anti-PD1). In this study, odetiglucan (OD), a novel beta glucan pathogen associated molecular pattern (PAMP), will be combined for the first time with CDX-1140, a fully human Ig2K agonistic monoclonal CD40 antibody in the maintenance setting after an induction phase of cytotoxic chemotherapy. OD and a CD40 agonist directly promote the activation and maturation of antigen presenting cells and shift the suppressive TME to enhance T-cell responses through non-redundant myeloid signaling pathways. We hypothesize that the combination of OD and CD40 agonist therapy has the potential to trigger anti-tumor immunity in PDAC and thus, extend and deepen responses to 1L cytotoxic chemotherapy. Methods: A two-part Phase 1b study of metastatic PDAC pts who have evidence of response or stable disease following 16-24 wks of chemotherapy is being conducted. Part A uses a 3+3 design; pts will receive OD 4 mg/kg QW + CDX-1140 1.5 mg/kg Q3W. Following a dose-limiting toxicity observation period, the dose will be held at 1.5 mg/kg or decreased to 0.72 mg/kg Q3W. Once preliminary safety is established, the cohort will be expanded to 15 pts. Part B pts will receive OD 4mg/kg + CDX-1140 at the dose identified in Part A Q3W. The study will enroll 30 pts. Main eligibility criteria: Metastatic PDAC having durable stable disease or response to 1L chemotherapy; serum ABA ≥20 µg/mL, and no prior anti-CD40 mAb or immunomodulatory treatment exposure. Primary endpoints are MTD, RP2D, and safety. Secondary endpoints include DOR, PFS, ORR, and OS and exploratory endpoints include evaluating immune pharmacodynamic responses in peripheral blood and tumor. Safety parameters will be listed and summarized using descriptive statistics. ORR will be tabulated by overall frequency; DOR, TTF, PFS and OS will be summarized and presented using Kaplan-Meier and waterfall plots. 5 US sites will participate. Clinical trial information: NCT04834778 .

The journey from melanocytes to melanoma.

Over the past decade, melanoma has led the field in new cancer treatments, with impressive gains in on-treatment survival but more modest improvements in overall survival. Melanoma presents heterogeneity and transcriptional plasticity that recapitulates distinct melanocyte developmental states and phenotypes, allowing it to adapt to and eventually escape even the most advanced treatments. Despite remarkable advances in our understanding of melanoma biology and genetics, the melanoma cell of origin is still fiercely debated because both melanocyte stem cells and mature melanocytes can be transformed. Animal models and high-throughput single-cell sequencing approaches have opened new opportunities to address this question. Here, we discuss the melanocytic journey from the neural crest, where they emerge as melanoblasts, to the fully mature pigmented melanocytes resident in several tissues. We describe a new understanding of melanocyte biology and the different melanocyte subpopulations and microenvironments they inhabit, and how this provides unique insights into melanoma initiation and progression. We highlight recent findings on melanoma heterogeneity and transcriptional plasticity and their implications for exciting new research areas and treatment opportunities. The lessons from melanocyte biology reveal how cells that are present to protect us from the damaging effects of ultraviolet radiation reach back to their origins to become a potentially deadly cancer.

Abstract 696: Sensitizing breast cancers to immune checkpoint inhibitors through CD27 agonism and vaccination against tumor-associated antigen

Abstract Project objective: Despite the recent revolution in immune checkpoint inhibitors (ICIs), only modest improvement in overall survival and likely caused by not enough potent cellular immunity among BC patients. Our lab has been focus on inducing cellular immunity against HER2+ BC through vaccination against the tumor-associated antigen HER2. Approximately 20 years ago, we performed an experimental pilot study by administrating HER2 peptide and recombinant protein pulsed dendritic cells (DC vaccine) to six patients with refractory HER2+ advanced or metastatic (stage II (≥ 6 +LN), III, or stage IV) BC. We followed the patients on 2019 found that all of the six patients were still alive, 18 years after vaccination. Their blood sample were analyzed with cytometry by time-of-flight (CyTOF) and found there is a significantly increased presence of CD27 expressing memory T cells in response to HER2 peptide stimulation. Recent report on the SARS-CoV2 mRNA vaccine also suggested that CD27 expressing memory T cells plays a critical role in long-lasting cellular immunity against SARS-CoV2 infection. Therefore, we hypothesized that CD27 plays a critical role in cellular immunity against BC, and the stimulation of CD27 expressing T cells with mAb targeting CD27 significantly increase the cellular immunity triggered by vaccination against tumor-associated antigen. Results: We recapitulate the rise of CD27+ antigen specific T cells among the vaccinated patients using a transgenic mouse model expressing human CD27. When combined the adenoviral-vector based HER2 (Ad-HER2) vaccination with a single dose of human aCD27 antibody (Varlilumab), we found there is a robust increase in the HER2 specific T cells compared to vaccination alone, especially CD27+CD44+ memory CD4 T cells, even after 120 days post vaccination. Using an ICI-insensitive syngeneic HER2+ BC models, we found 50% of mice in the combination group of aCD27 antibody plus Ad-HER2 showed total tumor regression by the end of study. When combined with anti-PD1 antibody, the combination of AdHER2 and Varlilumab leads to total tumor regression in 90% of tumor bearing mice with syngeneic HER2+ BC, indicating that the vaccination against tumor associated antigen HER2 plus anti-CD27 antibody sensitized ICI-insensitive HER2+ BC toward ICI. Conclusions: Our data demonstrates that the administration of anti-CD27 antibody significantly increase the long term presence of CD27+ antigen specific memory T cells after vaccination against tumor associated antigen HER2. As consequence, combination of anti-CD27 with HER2 sensitized the immune unresponsive breast cancer toward anti-PD1 antibody. Our study suggests that the vaccination against tumor-associated antigen with mAb targeting CD27 leads to the robust cellular immunity, which is required for successful ICIs against breast cancer. Citation Format: Bin-Jin Hwang, Erika Crosby, Timothy Trotter, Li-Chung Tsao, Tao Wang, Xiao Yang, Herbert Kim Lyerly, Zachary Hartman. Sensitizing breast cancers to immune checkpoint inhibitors through CD27 agonism and vaccination against tumor-associated antigen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 696.

A Real-World Comparison of Regorafenib and Trifluridine/Tipiracil in Refractory Metastatic Colorectal Cancer in the United States.

Trifluridine/Tipiracil (TAS-102) and regorafenib are FDA-approved in the United States for treatment of refractory metastatic colorectal cancer (mCRC). FDA approvals of these agents were based on modest improvements in overall survival (OS) compared with best supportive care + placebo in the RECOURSE and CORRECT trials, respectively. This study compared real-world clinical outcomes with the use of these agents. A nationwide deidentified electronic health record-derived database was reviewed for patients diagnosed with mCRC between 2015 and 2020. Patients who received at least 2 lines of standard systemic therapy followed by treatment with either TAS-102 or regorafenib were included for analysis. Kaplan-Meier and propensity score-weighted proportional hazards models were used to compare survival outcomes between groups. The records of 22,078 patients with mCRC were reviewed. Of these, 1,937 patients received at least 2 lines of standard therapy followed by regorafenib and/or TAS-102. Median OS for the TAS-102 alone or prior regorafenib group (n=1,016) was 6.66 months (95% CI, 6.16-7.18 months) compared with 6.30 months (95% CI, 5.80-6.79 months) for regorafenib alone or prior to TAS-102 (n=921; P=.36). A propensity score-weighted analysis controlling for potential confounders did not demonstrate a significant difference in survival between groups (hazard ratio, 0.99; 95% CI, 0.90-1.09; P=.82). A subgroup analysis did not identify any significant differences in outcomes regarding age, performance status, tumor sidedness, microsatellite instability status, or RAS/RAF status. This analysis of real-world data found that OS was similar for patients with mCRC who were treated with TAS-102 compared with regorafenib. Median OS with both agents in a real-world setting was similar to that shown in the clinical trials that led to their approvals. A prospective trial comparing TAS-102 and regorafenib would unlikely change current management of patients with refractory mCRC.

Abstract 2558: Determining the expression of RNA binding protein Rbm3 in tumor cells and immune cells in the tumor microenvironment in prostate cancer

Abstract Prostate cancer is the most common cancer among men. Currently, targeting the AR pathway, chemotherapy or immune-based therapies are major options but only provide a modest improvement in overall survival. RNA binding proteins have been shown to regulate AR expression in the progression of PCa. We and others have demonstrated that RNA binding protein RBM3 is upregulated in various solid tumors including PCa. We have also shown that RBM3 binds to 3’UTR of mRNAs of tumor-promoting factors and increases their mRNA stability and translation. However, the role of RBM3 in PCa is not well evaluated. We first analyzed the expression levels of RBM3 in the TCGA database. There was a significant increase in RBM3 expression even in cancers with a Gleason score of 6 upto Gleason 10 cancers. To confirm this we performed RT-PCR analyses of a prostate cancer cDNA panel. There was a significant increase in RBM3 expression in the PCa tissues compared to normal control. We used LNCaP and its derivative cell line C4-2B which show features of progressed disease such as metastatic capability and hormone independence. RT-PCR and western blot analyses demonstrated significantly higher RBM3 levels in C4-2B cells as compared to LNCaP cells suggesting a role for RBM3 in tumor progression. The tumor microenvironment also plays a very important role in prognosis of PCa. Specifically, tumor-associated macrophages (TAMs) have been shown to increase metastatic potential and increase tumor angiogenesis. To determine the levels of RBM3 expression and its effects on macrophage infiltration, we mined the TCGA database using TIMER2.0 software. There was a positive correlation of RBM3 expression with infiltration of both M1 and M2 macrophages. To further study the effect of interactions between PCa cells and TAMs, we used immortalized THP1 monocytes, which can be activated to M1 and M2 macrophages. We observed that just converting the THP1 cells to M1 or M2 macrophages increased RBM3 expression in both cell types. Also, when M1 and M2 macrophages were treated with conditioned media from LNCaP or C4-2B cells, there was an induction in the expression of RBM3. Similarly, when conditioned media from M0, M1, M2 activated THP1 cells were applied to LNCaP and C4-2B cells, there was an increase in RBM3 expression in the PCa cells. This suggests a positive cross-talk between the macrophages and PCa cells. We evaluated the cytokine profile in the conditioned media from M1 and M2 macrophages and determined that while M1 macrophages had increased levels of CXCL10, M2 macrophages showed higher levels of IL4 and IL10. Moreover, PCa cells have higher levels of CXCR3, the receptor for CXCL10. Together, these data suggest that crosstalk between TAMs and cancer cells in the PCA microenvironment plays a significant role in increasing RBM3 expression, which in turn enhances global translation of disease progression related genes. Citation Format: Afreen Asif Ali Sayed, David Standing, Prasad Dandawate, Shahid Umar, Roy Jensen, Rahul Parikh, John Taylor, Shrikant Anant. Determining the expression of RNA binding protein Rbm3 in tumor cells and immune cells in the tumor microenvironment in prostate cancer [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 2558.

A phase I clinical trial of trametinib in combination with TAS-102 in patients with chemotherapy-resistant RAS-mutated (PIK3CA/PTEN-wild type) metastatic colorectal cancer.

e15579 Background: TAS-102 was approved in 2015 after the phase III RECOURSE clinical trial demonstrated a modest improvement in overall survival in refractory metastatic colorectal cancer (mCRC). Preclinical models have shown synergistic activity between MEK inhibitors and TAS-102 in RAS-mutant (MT) and PIK3CA/PTEN wild-type (WT) models . We conducted a phase I study of trametinib plus TAS-102 in this molecularly selected refractory metastatic colorectal cancer patient population to explore the safety and efficacy of this combination. Methods: A 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with mCRC who progressed on prior standard therapies but with no prior TAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days. The primary endpoint of this study was to evaluate the maximum tolerated dose (MTD). Secondary objectives included an assessment of safety and toxicity of the combination regimen by CTCAE version 4.0 and any evidence of clinical activity including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) with this combination per RECIST guideline 1.1. Results: Between March 21, 2018, to March 19, 2020, 25 eligible patients were enrolled in this study. MTD was determined to be TAS-102 35 mg/m2 orally twice daily on days 1-5 and days 8-12 every 28 days with continuous trametinib dosing at 2mg orally daily. No patients achieved a partial or complete response. 5 of 21 evaluable patients (23.81%) achieved a stable disease response. Median PFS was 2 months (95% confidence interval (CI) 1.70-4.82) while median OS was 7 months (95% CI 6.36-11.48). Treatments were well tolerated with most common grade ≥ 3 adverse events being anemia (20%), neutropenia (12%), leukopenia (8%), diarrhea (8%), rash (4%), and fatigue (4%). Conclusions: Trametinib in combination with TAS-102 demonstrated a manageable safety profile however did not achieve meaningful clinical benefit in patients with RAS-MT and PIK3CA / PTEN-WT refractory mCRC. Research sponsor: Novartis. Clinical trial information: NCT03317119.

A real-world comparison of trifluridine/tipiracil and regorafenib in refractory metastatic colorectal cancer in the United States.

39 Background: For patients with refractory metastatic colorectal cancer (mCRC), both trifluridine/tipiracil (TAS-102) and regorafenib have received approval for use in the United States. The approvals of these agents were based on modest improvements in overall survival (OS) when compared to best supportive care plus a placebo in the RECOURSE and CORRECT trials, respectively. However, TAS-102 and regorafenib have never been directly compared in a prospective clinical trial. This study utilized a large real-world database to compare clinical outcomes with use of these agents. Methods: The nationwide de-identified Flatiron Health EHR-derived database was reviewed for patients diagnosed with mCRC between 2015 and 2020. Patients who received at least two lines of guideline recommended therapy for advanced disease followed by treatment with TAS-102 and/or regorafenib in the third line or greater were included for analysis. Patients who did not have a visit or medication order within 90 days of metastatic diagnosis were excluded to ensure patients were engaged with care at the data-providing institution. Kaplan-Meier and propensity score weighted models were used to compare survival outcomes between groups. Results: The records of 22,078 patients with mCRC were reviewed. Of the 4,407 patients that received at least two lines of standard therapy, 2,072 subsequently received regorafenib and/or TAS-102. Of these, 813 (39.2%) received TAS-102 alone, 275 (13.3%) TAS-102 followed by regorafenib, 736 (35.5%) regorafenib alone, and 248 (12.0%) regorafenib followed by TAS-102. Median OS for patients treated with TAS-102 alone or prior to receiving regorafenib was 6.66 months (95% CI 6.16-7.18) compared to 6.30 months (95% CI 5.80-6.79) for those treated with regorafenib alone or prior to receiving TAS-102 (p = 0.36). A propensity score weighted analysis controlling for age, race, stage at initial diagnosis, performance status at start of therapy, MSI/MMR status, RAS/RAF status, and line in which TAS-102 or regorafenib was received did not demonstrate a significant difference in survival between groups (HR 0.99, 95% CI: 0.90 -1.09, p = 0.82). A subgroup analysis did not identify any significant differences in outcomes stratified by age, performance status, MSI status, or RAS/RAF status. Conclusions: This analysis of real-world data did not identify a significant difference in survival outcomes in mCRC patients who were treated with TAS-102 or regorafenib. Median OS with both agents in a real-world setting was similar to that shown in the clinical trials that led to their approvals. This data should be considered when discussing the risks and benefits of TAS-102 and regorafenib with mCRC patients who are eligible for third line or greater treatment.

Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update.

To update recommendations of the American Society of Clinical Oncology (ASCO)-Ontario Health (Cancer Care Ontario [CCO]) adjuvant bone-modifying agents in breast cancer guideline. An Expert Panel conducted a systematic review to identify new, potentially practice-changing data. Four articles met eligibility criteria and form the evidentiary basis for revision of the previous recommendations. Adjuvant bisphosphonate therapy should be discussed with all postmenopausal patients (natural or therapy-induced) with primary breast cancer, irrespective of hormone receptor status and human epidermal growth factor receptor 2 status, who are candidates to receive adjuvant systemic therapy. Adjuvant bisphosphonates, if used, are not substitutes for standard anticancer modalities. The benefit of adjuvant bisphosphonate therapy will vary depending on the underlying risk of recurrence and is associated with a modest improvement in overall survival. The NHS PREDICT tool provides estimates of the benefit of adjuvant bisphosphonate therapy and may aid in decision making. Factors influencing the decision to recommend adjuvant bisphosphonate use should include patients' risk of recurrence, risk of side effects, financial toxicity, drug availability, patient preferences, comorbidities, and life expectancy. When an adjuvant bisphosphonate is used to prevent breast cancer recurrence, the therapeutic options recommended by the Panel include oral clodronate, oral ibandronate, and intravenous zoledronic acid. The Panel supports starting bisphosphonate therapy early, consistent with the points outlined in the parent CCO-ASCO guideline; this is a consensus recommendation. The Panel does not recommend adjuvant denosumab to prevent breast cancer recurrence, because studies did not show a consistent reduction of breast cancer recurrence in any subset of those with early-stage breast cancer.Additional information can be found at www.asco.org/breast-cancer-guideline.

Small-Cell Lung Cancer Long-Term Survivor Patients: How to Find a Needle in a Haystack?

Small-cell lung cancer (SCLC) is an aggressive malignancy characterized by a rapid progression and a high resistance to treatments. Unlike other solid tumors, there has been a scarce improvement in emerging treatments and survival during the last years. A better understanding of SCLC biology has allowed for the establishment of a molecular classification based on four transcription factors, and certain therapeutic vulnerabilities have been proposed. The universal inactivation of TP53 and RB1, along with the absence of mutations in known targetable oncogenes, has hampered the development of targeted therapies. On the other hand, the immunosuppressive microenvironment makes the success of immune checkpoint inhibitors (ICIs), which have achieved a modest improvement in overall survival in patients with extensive disease, difficult. Currently, atezolizumab or durvalumab, in combination with platinum–etoposide chemotherapy, is the standard of care in first-line setting. However, the magnitude of the benefit is scarce and no predictive biomarkers of response have yet been established. In this review, we describe SCLC biology and molecular classification, examine the SCLC tumor microenvironment and the challenges of predictive biomarkers of response to new treatments, and, finally, assess clinical and molecular characteristics of long-term survivor patients in order to identify possible prognostic factors and treatment vulnerabilities.

Update 2021: Management of Small Cell Lung Cancer.

Accounting for 14% of lung cancer, small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with rapid proliferation, early spread, and poor survival. We provide an overview of recent advances regarding SCLC pathogenesis, subtypes, and treatment development through literature review of key trials. There are no validated biomarkers or approved targeted treatments for this overly heterogeneous disease, but recent analyses have identified some promising targets and four major subtypes which may carry unique therapeutic vulnerabilities in SCLC. Treatment wise, only a third of patients present with limited stage SCLC, which can be managed with a combined modality approach with curative intent (usually chemo-radiotherapy, but in some eligible patients, surgery followed by systemic treatment). For advanced or extensive stage SCLC, combined chemotherapy (platinum-etoposide) and immunotherapy (atezolizumab or durvalumab during and after chemotherapy) has become the new standard front-line treatment, with modest improvement in overall survival. In the second-line setting, for disease relapse ≤ 6 months, topotecan, lurbinectedin, and clinical trials are reasonable treatment options; for disease relapse>6 months, original regimen, topotecan or lurbinectedin can be considered. Moreover, Trilaciclib, a CD4/CD6 inhibitor, was recently FDA-approved to decrease the incidence of chemotherapy-related myelosuppression in SCLC patients. While modest improvements in survival have been made especially in the metastatic setting with chemo-immunotherapy, further research in understanding the biology of SCLC is warranted to develop biomarker-driven therapeutic strategies and combinational approaches for this aggressive disease.

The Role of Immunotherapy in the Treatment of Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma is a rare and aggressive malignancy arising from mesothelial cells that line the serous membranes of the body. Cytotoxic chemotherapy has been a mainstay of therapy, resulting in a modest improvement in overall survival, but toxicity limits the eligible patient population. Few targeted agents beyond bevacizumab have demonstrated superior efficacy compared to placebos. With an improved understanding of the relationship between the immune system and cancer progression, immunotherapies are playing a greater role in the treatment of many cancers. Several early- and late-phase trials in malignant pleural mesothelioma, including assessments of the first-line efficacy of combination ipilimumab/nivolumab treatment, have now demonstrated promising results for both immune checkpoint inhibition and cell-based therapies. These immune therapies are likely to play a central role in the treatment of this disease going forward.

ES09.03 The Role of Biomarkers for Immunotherapy in the Adjuvant and Neoadjuvant Setting

For patients with NSCLC and absence of oncogenic addiction immune checkpoint inhibitors targeting PD1/PD-L1 change the therapeutic field. These treatments became standard of care in metastatic setting and are rapidly emerging in adjuvant and neoadjuvant setting. While more than 50% of patients with operable NSCLC will experience recurrence after surgery, neoadjuvant or adjuvant chemotherapy provides only a modest improvement in overall survival and could be highly toxic. Recent clinical trials underline the high rate of major pathological response in neoadjuvant setting and increase progression free survival in adjuvant setting. While such data will rapidly be practice changing immune checkpoint inhibitors are not effective in all patients and like in metastatic setting biomarkers remains unmet need. Various biomarkers are currently testing going from simple clinical biomarkers, to complex genomic and transcriptomic tests. Most biomarkers seem to behave similarly in adjuvant/neoadjuvant setting and in metastatic setting. Clinical patient’s characteristics are important to predict efficacy of adjuvant or neoadjuvant treatment. In IMPOWER 10 trial, testing adjuvant treatment with atezolizumab, oncogenic addiction with EGFR mutation or ALK translocation are associated with absence of efficacy of atezolizumab (1). Tumor with EGFR and ALK genomic alteration tumor are frequently poorly infiltrated in CD8 T cells and present poor level of mutations which render them resistant to immune checkpoint inhibitors. PD-L1 is also an important biomarker of efficacy in early NSCLC. In Checkmate 816 trial (2) which tests neoadjuvant chemotherapy versus nivolumab plus chemotherapy underlines that PD-L1 >1% is associated with higher rate of pathological complete response but nivolumab enhance efficacy of chemotherapy in either PD-L1 positive or negative tumors. In contrast in IMPOWER 10 trial (1), atezolizumab improves progression free survival only in patients with PD-L1 positive tumors. Efficacy proportionally increase with PD-L1 expression. Interestingly, similar observation was previously performed in PACIFIC trial (3). Importantly, a post-hoc analysis underlines that durvalumab give survival benefit only in PD-L1 positive patients raising question on this utility in this subset of patients. Smaller studies testing anti PD-1 alone or in association with anti CTLA-4 in neoadjuvant setting observed major responses irrespective of PD-L1 status (4,5). So, PD-L1 expression is an imperfect surrogate marker of hot tumors richly invaded by anti tumoral CD8 T cells. Such data underline the difficulty to use PD-L1 to avoid immune checkpoint inhibitors usage. In addition, PD-L1 assessment in neoadjuvant setting only relies on a tumor biopsy which is an imperfect surrogate marker of PD-L1 expression in the whole tumor. Tumor mutational burden (TMB) represents the total number of mutation found in coding region of cancer cell genome. High number of mutation is correlated with high capacity of cancer cells to present neoantigens, and cancers cells which present high level of neoantigen are more easily recognized by T cells. In CHECKMATE 816 (2) high TMB is associated with better response to neoadjuvant immunotherapy (pathological complete response of 22.44% for TMB low and 30.8% for TMB high). Similarly, in a small study using nivolumab and ipilimumab in neoadjvuvant setting, there was a significant correlation between the pathological response and the pretreatment TMB (5). Additional works are awaiting to determine if HLA status or intratumoral heterogeneity are also important to predict response to adjuvant or neoadjuvant immunotherapy like in metastatic setting. In addition to such classical biomarkers some emerging biomarkers are described in small cohort of neoadjuvant immunotherapy. Gut microbiome could influence response to checkpoint inhibitors by different mechanisms like modulation of tumor microenvironement or bacterial mimicry. In NEOSTAR trial (4), higher abundance of Akkermansia in baseline samples of gut microbiote is associated with better response to nivolumab + ipilimumab and is positively correlated with intratumoral immune response. Similarly, Akkermansia was also associated with favorable clinical outcomes in patients with melanoma, NSCLC and renal cell carcinoma receiving immunotherapy in metastatic setting thus confirming the important role of gut microbiota and akkermansia in the response to immunotherapy.

Time Interval to Initiation of Whole-Brain Radiation Therapy in Patients With Small Cell Lung Cancer With Brain Metastasis

PurposePatients with small cell lung cancer (SCLC) who have brain metastases require whole-brain radiation therapy (WBRT). When there is no emergent indication for WBRT, patients may receive systemic therapy first and WBRT afterward. In scenarios when systemic therapy is initiated first, it has not been previously investigated whether delaying WBRT is harmful. Methods and MaterialsThe National Cancer Database was queried (2004-2016) for patients with SCLC with brain metastases who received 30 Gy in 10 fractions of WBRT. Patients were divided into groups based on whether they received early WBRT (3-14 days after initiation of chemotherapy) or late WBRT (15-90 days after initiation of chemotherapy). Demographic and clinicopathologic categorical variables were compared between those who had early WBRT (3-14 days) and those who had late WBRT (15-90 days). Factors predictive for late WBRT were determined. Overall survival (OS), which was defined as days from diagnosis to death, was evaluated and variables prognostic for OS were determined. ResultsA total of 1082 patients met selection criteria; 587 (54%) had early WBRT and 495 (46%) received late WBRT. Groups were similarly distributed aside from days from initiating chemotherapy to initiating WBRT (P < .001). The early WBRT group had a median of 7 days (interquartile range [IQR], 5-10 days) from initiating chemotherapy to initiating WBRT and the late WBRT group had a median of 34 days (IQR, 21-57 days). On binary logistic regression analysis, a longer time interval between diagnosis and the start of systemic therapy was predictive for later WBRT. Median OS was 8.7 months for early WBRT and 7.5 months for late WBRT (hazard ratio [HR], 1.165; P = .008). Early WBRT (P = .02), female sex (P = .045), and private insurance (P = .04) were favorable prognostic factors for OS on multivariable analysis, whereas older age (P = .006) was an unfavorable prognostic factor. ConclusionsPatients with SCLC and brain metastases who received early WBRT were found to have a modest improvement in OS compared with patients who received late WBRT. These findings suggest that early WBRT should be offered to patients who have brain metastases, even in the absence of an indication for emergent WBRT.

Where to Start and What to Do Next: The Sequencing of Treatments in Metastatic Esophagogastric Cancer.

Esophagogastric cancer is associated with rising incidence and high mortality. Nearly 40% of patients have metastatic disease at the time of diagnosis with poor 5-year overall survival. The treatment of squamous cell carcinoma of the esophagus and gastroesophageal adenocarcinoma has started to bifurcate in recent years, owing to the evolving understanding of the biologic and genomic characteristics of these tumors. Incorporation of HER2-directed therapy in the form of monoclonal antibody and antibody-drug conjugate is now standard of care for patients with HER2-positive disease. The addition of immune checkpoint inhibitors to the therapeutic landscape of metastatic esophagogastric cancer is associated with modest improvement in overall survival, and definition of predictive biomarkers of response to checkpoint inhibition remains imprecise. A number of therapeutic targets including FGFR2b, Claudin 18.2, DKK-1, and DNA repair defects are being explored in clinical trials. Similarly, combination immunotherapy and novel HER2-targeting agents, such as bispecific antibody and small-molecule inhibitors, are at various stages of clinical development. Despite the progress made in the field of targeted therapies and checkpoint inhibition, chemotherapy remains an integral part of treatment of metastatic esophagogastric cancer but is associated with considerable toxicity. Clinical trials focusing on minimizing toxicity of currently available therapeutic agents, development of novel biomarker-driven treatment strategies, and overcoming resistance to immune checkpoint inhibition will define the future of this traditionally indelible disease.

Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer.

Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer.

Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer.

Immunotherapies have shown remarkable success in the treatment of multiple cancer types; however, despite encouraging preclinical activity, registration trials of immunotherapy in prostate cancer have largely been unsuccessful. Sipuleucel-T remains the only approved immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer based on modest improvement in overall survival. This immune evasion in the case of prostate cancer has been attributed to tumor-intrinsic factors, an immunosuppressive tumor microenvironment, and host factors, which ultimately make it an inert ‘cold’ tumor. Recently, multiple approaches have been investigated to turn prostate cancer into a ‘hot’ tumor. Antibodies directed against programmed cell death protein 1 have a tumor agnostic approval for a small minority of patients with microsatellite instability-high or mismatch repair-deficient metastatic prostate cancer. Herein, we present an overview of the current immunotherapy landscape in metastatic castration-resistant prostate cancer with a focus on immune checkpoint inhibitors. We describe the results of clinical trials of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer; either as single agents or in combination with other checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, novel hormonal therapies, chemotherapies, and radioligands. Finally, we review upcoming immunotherapies, including novel monoclonal antibodies, chimeric-antigen receptor (CAR) T cells, Bi-Specific T cell Engagers (BiTEs), therapies targeting the adenosine pathway, and other miscellaneous agents.