Upfront Combination Chemotherapy Research Articles

Targeting PEA3 transcription factors to mitigate small cell lung cancer progression

Small cell lung cancer (SCLC) remains a lethal disease with a dismal overall survival rate of 6% despite promising responses to upfront combination chemotherapy. The key drivers of such rapid mortality include early metastatic dissemination in the natural course of the disease and the near guaranteed emergence of chemoresistant disease. Here, we found that we could model the regression and relapse seen in clinical SCLC in vitro. We utilized time-course resolved RNA-sequencing to globally profile transcriptome changes as SCLC cells responded to a combination of cisplatin and etoposide—the standard-of-care in SCLC. Comparisons across time points demonstrated a distinct transient transcriptional state resembling embryonic diapause. Differential gene expression analysis revealed that expression of the PEA3 transcription factors ETV4 and ETV5 were transiently upregulated in the surviving fraction of cells which we determined to be necessary for efficient clonogenic expansion following chemotherapy. The FGFR-PEA3 signaling axis guided the identification of a pan-FGFR inhibitor demonstrating in vitro and in vivo efficacy in delaying progression following combination chemotherapy, observed inhibition of phosphorylation of the FGFR adaptor FRS2 and corresponding downstream MAPK and PI3K-Akt signaling pathways. Taken together, these data nominate PEA3 transcription factors as key mediators of relapse progression in SCLC and identify a clinically actionable small molecule candidate for delaying relapse of SCLC.

Review and Updates on Approaches to Neoadjuvant Chemotherapy in Rectal Cancer

The currently established standard of care treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) and adjuvant fluorouracil and oxaliplatin. The body of evidence that supports this treatment has grown over the last 20 years. However, recent advances and ongoing studies seek to further evaluate the role of neoadjuvant chemotherapy with and without radiation and total neoadjuvant therapy (TNT). In this article, we review the current literature as well as investigate the emerging role of TNT for patients with LARC and comment on updates utilizing combination neoadjuvant chemotherapy in early-stage rectal cancer. Evidence for the current standard of neoadjuvant CRT comes from well-established randomized phase III trials as well as emerging evidence on merits of TNT. There is a growing body of literature including retrospective analysis and ongoing clinical trials that look at upfront induction chemotherapy in addition to CRT prior to surgical resection leading to more effective delivery of systemic therapy and increases in response to treatment. Neoadjuvant combination chemotherapy is also being investigated in early-stage low rectal tumors to see if rates of local excision will increase compared to radical excision. Current evidence continues to support neoadjuvant CRT as the standard treatment for LARC. There is an increasing body of evidence to support TNT in LARC as an effective treatment strategy that better ensures delivery of systemic therapy leading to higher rates of complete response (CR) and is encouraging for the development of non-operative protocols. There is ongoing evaluation looking at the benefit of novel sensitizers added to neoadjuvant therapy and ongoing investigation into upfront combination chemotherapy with selective use of radiation in upper rectal cancers.

Impact of age on efficacy and early mortality of initial sequential treatment versus upfront combination chemotherapy in patients with metastatic colorectal cancer: a subgroup analysis of a phase III trial (AIO KRK0110, XELAVIRI study)

IntroductionThe XELAVIRI study compared application of fluoropyrimidine (FP) and bevacizumab (Bev) followed by sequential escalation to irinotecan (Iri), FP and Bev (arm A) to upfront combination therapy with FP, Iri and Bev (arm B) in patients with metastatic colorectal cancer (mCRC). To elucidate the impact of age on survival, we evaluated efficacy and early mortality in the underlying trial. MethodsPatients were stratified for age in three cohorts (<65 years, 65–74 years and ≥75 years). Survival end-points were expressed by the Kaplan-Meier method and compared by log-rank testing and Cox regression. Objective response and 60-day mortality were evaluated by chi-square testing. ResultsThe efficacy analyses suggest more substantial benefit from upfront combination chemotherapy in younger patients with mCRC. Elderly patients (≥75 years) derived limited benefit from upfront combination chemotherapy, particularly in terms of overall survival. Of 421 randomised patients, 13 patients (3.1%) died within 60 days after treatment initiation with the highest prevalence in elderly patients (1.6% < 65 years, 2.8% 65–74 years and 5.2% ≥ 75 years, p = 0.26). The frequency of 60-day mortality was significantly associated with age (with a maximum of 8.7% in patients aged ≥75 years) in patients undergoing upfront combination therapy (p = 0.027) but not in patients receiving sequential treatment (p = 0.63). ConclusionCombination therapy with FP, Iri and Bev does not substantially improve the outcome of patients aged ≥75 years as compared with sequential treatment algorithm. These patients appear to be at a relevant risk for 60-day mortality under Iri-based combination chemotherapy plus Bev.

Abstract 1880: Validation of protein arginine methyltransferase 5 (PRMT5) as a candidate therapeutic target in the canine model of non-Hodgkin lymphoma

Abstract Introduction: Lymphoma is a common, aggressive malignancy in dogs. While generally responsive to upfront combination chemotherapy with traditional cytotoxic drugs, remission times are short and cures rare. New treatment strategies are therefore needed. Protein arginine methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase (PRMT) enzyme whose relevance to cancer biology has become increasingly evident as more studies have shown this enzyme to be involved in the regulation of multiple major signaling pathways affecting cell death, proliferation, and malignant transformation. While the mechanism behind many of these cell-transforming capabilities of PRMT5 remains unknown, knockdown of PRMT5 expression by genetic or pharmacologic means has been shown to modulate the methylation status of target proteins and exert antitumor effects in vitro and in vivo. Consequently, PRMT5 small-molecule inhibitors are in early preclinical development. Methods: In this study, we characterized patterns of PRMT5 expression and correlated these with histologic subtype using canine lymphoma tissue microarrays (TMAs). We characterized expression of PRMT5 in canine lymphoma tissues and methylation targets in canine B-cell lymphoma cell lines and treated them with different PRMT5 inhibitors to determine effects on PRMT5, target proteins and antitumor activity. We also assessed PRMT5 inhibition ex vivo in patient B-cell lymphomas via flow cytometry and assessment of apoptosis with annexin V/PI staining. Results: Canine diffuse large B-cell lymphoma showed cytoplasmic staining for PRMT5 (48.8% strong, 50.0% weak, n = 165) compared to negative or weak staining in normal and hyperplastic lymph nodes (n = 40). Lymphoblastic T-cell lymphoma samples showed strong nuclear staining (40%, n= 10). No nuclear staining was appreciated in normal or hyperplastic lymph nodes. Similarly, canine B-cell lines showed high expression of PRMT5. PRMT5 small-molecule inhibitors inhibited growth of CLBL-1 and 17-71 canine lymphoma cell lines. Histone (H3R8 and H4R3) methylation status was suppressed at their respective IC50s. Ex vivo treatment of canine patient tumor cells showed suppression of growth at 24 hours. Conclusion: We have demonstrated that PRMT5 is expressed in canine lymphomas and that PRMT5 inhibition can suppress the growth of canine lymphoma cells, supporting the continued use of the spontaneous canine lymphoma model for the preclinical development of PRMT5 inhibitors. Citation Format: Kyle A. Renaldo, Lindsay E. Courtney, Konstantin Shilo, Robert A. Baiocchi, William C. Kisseberth. Validation of protein arginine methyltransferase 5 (PRMT5) as a candidate therapeutic target in the canine model of non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1880.

Abstract 39: XPO1 inhibitor, KPT-8602, is well tolerated and highly active against AML blasts and LICs

Abstract Standard chemotherapy often induces remissions in AML patients, but the disease frequently relapses due to incomplete targeting of leukemia-initiating cells (LICs), emphasizing the need for novel effective treatments. An attractive target for AML therapy is nuclear exporter exportin 1 (XPO1), which mediates continuous nuclear export of a subset of proteins and RNAs. The orally bioavailable XPO1 inhibitor of the Selective Inhibitor of Nuclear Export (SINE) class of compounds, selinexor (KPT-330), is currently in phase 1 and 2 clinical trials in adult patients with AML and in phase 1 trials for relapsed childhood ALL and AML. The results of these trials are encouraging, as they have demonstrated that selinexor is active in inducing remission in patients with relapsed or refractory disease. Here we report the antileukemic efficacy and tolerability of KPT-8602, a second-generation XPO1 inhibitor. KPT-8602 demonstrates substantially reduced brain penetration compared to selinexor, with resultant attenuation of the CNS-mediated side effects of anorexia and weight loss. Due to its improved tolerability profile, KPT-8602 can be given daily compared to the two- or three-times-weekly regimen of selinexor. To define the antileukemia activity of KPT-8602 against primary AML blasts and LICs in a relevant preclinical setting, we established patient-derived xenograft (PDX) models, in which leukemic blasts from AML patients with poor-prognosis disease (cytogenetically normal AML with FLT3-ITD (AML-CN), AML with complex karyotype (AML-CK), and MDS-derived AML (MDS/AML) are transplanted into immunodeficient NOD-SCID-IL2Rcgnull (NSG) mice. Mice engrafted with leukemic blasts are treated with vehicle, selinexor (20 mg/kg three times per week), or KPT-8602 (15 mg/kg daily for 4 weeks). KPT-8602 exhibits superior antileukemic activity and better tolerability in the AML PDX models tested, with nearly complete elimination of human AML cells in AML-CN model. To determine the frequency of LICs in the vehicle control, selinexor or KPT-8602, we used a limiting dilution transplantation assay. Although both selinexor and KPT-8602 effectively targeted LICs, KPT-8602 is more potent in eliminating LICs, as evidenced by a more profound reduction of LIC frequency in the AML-CK and AML-CN PDX models (507-fold vs. 0.9-fold reduction in AML-CK, P&amp;lt;0.0001; and 437-fold vs. 111-fold reduction in AML-CN by KPT-8602 vs. selinexor, P=0.79). The impact on normal human hematopoietic stem and progenitor cell (HSPC) fractions by CD34/CD38 flow analysis and limiting dilution transplantation assays (performed by the same methodology as described for PDX models of AML) demonstrates that, in contrast to its profound effects against AML LIC, KPT-8602 does not preferentially kill normal HSPC, providing a therapeutic window for elimination of relapse-driving LICs while sparing normal HSPCs. KPT-8602 has entered a phase 1/2 trial in patients with relapsed/refractory multiple myeloma. Our preclinical results indicate that KPT-8602 should be tested in clinical trials to determine its toxicity and efficacy in patients with relapsed or refractory AML, with the hope that it can eventually be integrated into upfront combination chemotherapy regimens. To delineate the pathways that mediate the apoptotic signaling in response to the SINE compounds, we are conducting the RNA-seq, ChIP-seq and ATAC-seq studies on AML cell lines treated in vitro as well as AML cells isolated from PDX mice. The preliminary results of these studies will be presented at the meeting. Citation Format: Julia Etchin, Alla Berezovskaya, Amy S. Conway, Ilene A. Galinsky, Richard M. Stone, Erkan Baloglu, William Senapedis, Yosef Landesman, Michael Kauffman, Sharon Shacham, Jean CY Wang, A Thomas Look. XPO1 inhibitor, KPT-8602, is well tolerated and highly active against AML blasts and LICs [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 39.

Cellular immune biomarkers to prognosticate for survival to adoptive T-cell therapy in advanced nasopharyngeal cancer.

6047 Background: We have published a Phase II clinical trial in 35 advanced incurable stage 4c NPC patients employing upfront first line chemo-immunotherapy of four cycles of gemcitabine and carboplatin, followed by six cycles of adoptive transfer autologous EBV-specific cytotoxic T lymphocytes (CTL). The 2- and 3-year overall survival rates were 62.9 and 37.1% respectively, which represent the best reported survival outcome for first-line treatment of advanced NPC when compared to historical clinical trials. Methods: From this Phase II trial, we completed serial multiple deep immune phenotyping analyses including flow cytometry, nanostring, and multiplex ELISA assays. We then investigated how these factors influence and determine successful therapy using 2-year survival rates. Results: Longitudinal modular transcriptome analysis of patient PBMCs revealed significant increases in T cell, NK, and B cell modules post chemotherapy within the 2-year survivor group. Administration of CTLs restored expression of lymphocyte transcripts in the non-survivor group at 2-weeks post infusion. However, as immunotherapy proceeded, 2-year survivors displayed significant increases in multiple lymphocyte module associated transcripts. These immune correlates were associated with increased IFN-γ and decreased myeloid chemokine concentrations in peripheral sera during immunotherapy in 2-year survivors. Longitudinal immunophenotyping of patient PBMCs at serial timepoints showed that 2-year survivors displayed significant decreased amounts of monocytic myeloid-derived suppressor cells (mMDSCs), compared to non-survivors after chemotherapy, which subsequently determined successful CTL immunotherapy survival benefit. Conclusions: This is the first report in human cancer patients that successful adoptive T cell immunotherapy correlates with lower mMDSCs following chemotherapeutic preconditioning. We have also identified potential prognostic immune biomarkers that effectively predicts efficacy of CTL immunotherapy, following upfront combination chemotherapy, and thus survival. Lymphodepletion with chemotherapy appears to be vital for adoptive T cell therapy efficacy.

Strategies of sequential therapies in unresectable metastatic colorectal cancer: a meta-analysis.

Before the emergence of first-line combination chemotherapy, the standard of care for unresectable metastatic colorectal cancer (mcrc) was first-line monotherapy with modulated 5-fluorouracil. Several large phase iii randomized controlled trials, now completed, have assessed whether a planned sequential chemotherapy strategy-beginning with fluoropyrimidine monotherapy until treatment failure, followed by another regimen (either monotherapy or combination chemotherapy) until treatment failure-could result in the same survival benefit produced with an upfront combination chemotherapy strategy, but with less toxicity for patients. The medline and embase databases, and abstracts from meetings of the American Society for Clinical Oncology and the European Society for Medical Oncology, were searched for reports comparing a sequential strategy of chemotherapy with an upfront combination chemotherapy in adult patients with mcrc. Publications that reported efficacy or toxicity data (or both) were included. The five eligible trials that were identified included 4532 patients. A meta-analysis of those trials demonstrates a statistically significant survival advantage for combination chemotherapy (hazard ratio: 0.92; 95% confidence interval: 0.86 to 0.99). However, the median survival advantage (3-6 weeks in most trials) is small and of questionable clinical significance. Three trials reported first-line toxicities. Upfront combination chemotherapy results in significantly more neutropenia, febrile neutropenia, thrombocytopenia, diarrhea, nausea, vomiting, and sensory neuropathy. Sequential chemotherapy results in significantly more hand-foot syndrome. Given the small survival advantage associated with upfront combination chemotherapy, planned sequential chemotherapy and upfront combination chemotherapy can both be considered treatment strategies. Treatment should be chosen on an individual basis considering patient and tumour characteristics, toxicity of each strategy, and patient preference.

Metastatic Site in Pancreatic Adenocarcinoma Correlates with Prognosis

Context Pancreatic adenocarcinoma (PA) is mostly metastatic at time of diagnosis with a poor survival. Objective We decided to explore whether metastatic site correlates with prognosis. Methods Patients with pathologic diagnosis of metastatic PA, treated at our Institution with upfront combination chemotherapy between April 1997 and August 2010 were eligible for this analysis. Baseline tumor assessment consisted of contrast enhanced computed tomography scan of the abdomen and the thorax. Results Two-hundreds and sixty-five patients with metastatic PA, median age 60 years; median PS 90; median CA 19-9 1,048 were eligible; 19 (7.2%) had prior pancreatic surgery. Metastases were located: in a single organ (n=150; 56.6%); liver (n=227; 85.3%); peritoneum (n=32; 12.1%); lung (n=53; 19.9%). Lung was the only metastatic site in 15 cases (5.6%). Median and 1-year overall survival (OS) was 9.0 months and 32.2%. Prior surgery correlated with better OS (11.7 and 51.0% versus 8.9 and 30.8%; P=0.006); liver metastases with worse OS (median and 1-year OS: 8.8 months and 29.7% versus 11.1 and 47.4%; P=0.005); while no difference in OS was observed based on number of metastatic sites (P=0.37); peritoneal (P=0.50) or lung metastases (P=0.10). Patients with lung as isolated metastatic site lived longer (17.3 months and 66.7%) with respect to the whole population (9.0 months and 30.1%; P=0.01) and to patients with lung metastases associated to other metastatic sites (8.8 months and 34.2%; P=0.07). Conclusions Prior surgery and metastatic site correlate with prognosis and should be used as a stratification criterion in prospective trials. Patients with lung as isolated metastatic site has a particularly good prognosis.

Metastatic Extraosseous Ewing's Sarcoma (EES)/Primitive Neuroectodermal Tumor (PNET) of the Kidney: 8-Year Durable Response After Induction and Maintenance Chemotherapy

Clinical Practice Points •Extraosseous Ewing's sarcomas (EES)/primitive neuroectodermal tumors (PNET) of the kidney are rare. •They are classified within the Ewing's sarcoma family of tumors (ESFT) and include those arising from the kidney. •We report a patient who presented with metastatic EES/PNET of the kidney, was treated with chemotherapy without local therapy, and achieved a durable clinical remission that has lasted longer than 8 years. •This case report illustrates the importance of obtaining a biopsy of a kidney tumor that appears atypical for renal cell cancer and promptly initiating upfront combination chemotherapy, if the diagnosis of EES/PNET is confirmed. •The role of cytoreductive nephrectomy (CN) is not defined in this patient population. •We believe that long-term disease-free survival can be achieved with chemotherapy alone. •CN may not be necessary in the management of patients with metastatic EES/PNET of the kidney, and may limit the ability to administer intensive chemotherapy regimens such as high-dose ifosfamide. •Extraosseous Ewing's sarcomas (EES)/primitive neuroectodermal tumors (PNET) of the kidney are rare. •They are classified within the Ewing's sarcoma family of tumors (ESFT) and include those arising from the kidney. •We report a patient who presented with metastatic EES/PNET of the kidney, was treated with chemotherapy without local therapy, and achieved a durable clinical remission that has lasted longer than 8 years. •This case report illustrates the importance of obtaining a biopsy of a kidney tumor that appears atypical for renal cell cancer and promptly initiating upfront combination chemotherapy, if the diagnosis of EES/PNET is confirmed. •The role of cytoreductive nephrectomy (CN) is not defined in this patient population. •We believe that long-term disease-free survival can be achieved with chemotherapy alone. •CN may not be necessary in the management of patients with metastatic EES/PNET of the kidney, and may limit the ability to administer intensive chemotherapy regimens such as high-dose ifosfamide.

Outcome of upfront combination chemotherapy followed by chemoradiation for locally advanced pancreatic adenocarcinoma

The role and timing of chemotherapy and radiation for treating stage III pancreatic adenocarcinoma remains controversial. Treatment-naive patients with stage III non-resectable pancreatic adenocarcinoma were treated with PEFG/PEXG (cisplatin, epirubicin, 5-fluorouracil (F)/capecitabine (X), gemcitabine) or PDXG (docetaxel substituting epirubicin) regimen for 6 months followed by radiotherapy (50-60 Gy) with concurrent F or X or G. Ninety-one patients were registered between April 1997 and December 2007. Forty-three patients (47%) had a partial remission and 38 (42%) had a stable disease. Thirteen patients (14%) were radically resected yielding one pathologic complete remission. Median survival (OS) was 16.2 months. Median progression-free survival was 9.9 months. Pattern of failure consisted of isolated local failure (N = 26, 35%); both local and systemic failure (N = 14, 19%); isolated systemic failure (N = 35, 47%). Combination chemotherapy with four-drug regimens followed by chemoradiation was a feasible strategy showing relevant results in stage III pancreatic adenocarcinoma.

Short-course preoperative radiotherapy with delayed surgery in rectal cancer – A retrospective study

Purpose In the most advanced, non-resectable primary rectal cancers, conventional long-course radiotherapy (RT) (1.8–2 Gy × 25–28), frequently combined with chemotherapy, has been used since tumour regression is needed in order to allow a radical (R0) resection. In Uppsala, short-course 5 × 5 Gy with planned delayed surgery has been used in patients with contraindications to long-course RT (±chemotherapy). The aim is to describe our experience of using this approach in patients not eligible for standard treatment. Patients and methods During 2002 and 2005, 46 patients with non-resectable rectal cancer (±synchronous distant metastases) were treated with 5 × 5 Gy and delayed surgery if possible. The clinical records were retrospectively evaluated. The first group (A) had no metastases (T4NXM0), whereas the other two groups (B + C) had metastases (T4NXM1). In group (B), the patients had predominantly loco-regional disease and were not candidates for combination chemotherapy (high age, co-morbidities), and in group (C) up-front combination chemotherapy was given, with the intention to have surgery of both the primary and the secondaries if sufficient regression at both sites were seen. Results The patients in the first two groups (A + B) were old (median 79 and 76 years, respectively), and had several co-morbidities. In group (C), median age was 63 years. The 5 × 5 Gy RT was well tolerated by most patients, but grade IV diarrhoea was recorded in three elderly patients. One patient in the group (C) died from neutropenic fever. Many patients were reported to have less local symptoms after the treatment given. Delayed surgery was performed in all but nine patients. Radical surgery (R0 + R1) was performed in 22 (92%) (group A), 4 (44%) (group B), and 6 (46%) (group C) patients, respectively. A pCR was seen in four patients (two in group A and two in group C). No postoperative deaths occurred. Conclusions Considering the very high age and presence of co-morbidity, the 5 × 5 Gy schedule is well tolerated. Further, considering the very advanced local stage, the schedule has considerable anti-tumour activity and can result in radical surgery in a high proportion of patients.