Chemotherapy-based Treatments Research Articles

Emerging chemotherapy-based treatments in anaplastic thyroid cancer: an updated analysis of prospective studies.

For patients with anaplastic thyroid cancer (ATC) without mutational driver genes, chemotherapy is suggested to be the first-line treatment option. However, the benefits of chemotherapy in treating ATC are limited. In this analysis, we collected the prospective data reported since 2010 to analyze the emerging chemotherapy-based treatments in ATC comprehensively. For this updated analysis, we searched PubMed (MEDLINE), Web of Science, Embase, and Cochrane CENTRAL databases from 1 January 2010 to 7 February 2024 for prospective clinical studies that contained chemotherapy-based treatments. This analysis was done to pool overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), disease control rates (DCRs), and grade 3 or worse treatment-related adverse events (TRAEs). Six prospective clinical trials with 232 patients were included. Chemotherapy was commonly combined with targeted therapy or radiotherapy. The pooled median OS was 6.0 months (95% CI 4.1-9.7), and the median PFS was 3.2 months (95% CI 1.9-6.0) in patients with ATC who received chemotherapy-based strategies. The integrated ORR and DCR were 21% (95% CI 15%-27%) and 64% (95% CI 55%-72%), respectively. Regarding the grade 3 or worse TRAE, the pooled incidence was 68% (95% CI 47%-86%). Although the emerging chemotherapy-based treatments showed antitumor activity in patients with ATC, these strategies failed to prolong the survival time substantially. More practical, safe, and novel therapeutic regimens for patients with ATC warrant further investigations.

Abstract 4103: Novel mRNA-encoded HPV vaccine with APC maturation signal and endolysosomal trafficking domain demonstrates superior T cell-mediated immunogenicity and efficacious tumor clearance in vivo

Abstract Human Papillomavirus (HPV), particularly HPV16, is a known causative agent of cancers in various anatomical sites, notably the anogenital and oropharyngeal regions. Despite the availability of prophylactic HPV vaccines for almost two decades, vaccination rates among young females, who are at a heightened risk for cervical intraepithelial neoplasia (CIN) and subsequent invasive cancer, remain suboptimal. The current standard of care for cervical cancer, involving invasive surgery and chemotherapy-based treatments, underscores the pressing need for safer and more effective therapeutics to enhance patient survival and quality of life. In this context, while several HPV16-E6/E7 targeted therapeutic vaccines are in development and clinical trials, their clinical efficacy has been limited due to inadequate antigen presentation and suboptimal immunogenicity. Addressing this, our team has developed a novel, highly immunogenic mRNA therapeutic cancer vaccine, engineered to activate a robust T cell-mediated adaptive immune response and exhibit strong anti-tumor potential. Our innovative approach includes the design of an HPV16-E6/E7 mRNA vaccine (ABO2101) that incorporates a unique antigen-expressing cassette. This cassette features endolysosomal trafficking domains and antigen presenting cell (APC) activation stimulators, enhancing both Class I and Class II antigen presentation and APC maturation, thereby amplifying antigen-specific T cell responses. In both murine and human-derived experimental models, ABO2101 has demonstrated a significantly more potent adaptive T cell response against HPV16 antigens compared to other HPV16 mRNA therapeutic vaccines. In antitumor efficacy evaluations using TC-1 tumor-bearing mice, ABO2101 single-dose administration successfully eradicated both early-stage (50 mm³) and advanced (500 mm³) tumors. This was accompanied by a marked increase in HPV16-specific CD8+ cytotoxic T lymphocytes within the tumor microenvironment. Moreover, in prophylactic and adjuvant therapy models, ABO2101 prevented tumor growth across various dosages, indicating its robust preventative capabilities. Further, the combination of ABO2101 with immune checkpoint inhibitors, including PD-1 and CTLA-4 antibodies, displayed a synergistic effect in both immune-oncology sensitive and resistant animal models, suggesting a potential for combinational clinical therapy. In conclusion, our development of ABO2101, a mRNA-based HPV16-E6/E7 therapeutic cancer vaccine inclusive of APC maturation signals, represents a groundbreaking advancement in HPV-associated cancer treatment, as supported by our compelling preclinical data. Citation Format: Liang Du, Hongya Han, Jingshu Ma, Zhenxing Yang, Jinjuan Mao, Jijun Yuan, Bo Ying. Novel mRNA-encoded HPV vaccine with APC maturation signal and endolysosomal trafficking domain demonstrates superior T cell-mediated immunogenicity and efficacious tumor clearance in vivo [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 4103.

Abstract B145: Clinical features of progression and outcomes with subsequent therapies in patients treated with RET-inhibitors

Abstract Background: RET fusions can be found in 1-2% of patients (pts) with advanced non-small cell lung cancer (aNSCLC). While targeted treatment with RET inhibitors (RETi) has significantly improved prognosis, resistance eventually develops. Current knowledge regarding the pattern of disease progression and the optimal therapeutic sequence for patients treated with RETi is limited. Methods: We conducted a retrospective multicentric collection of clinical and biological data on pts with RET-rearranged (RET+) aNSCLC treated with first-generation RETi. Patients with a progression-free survival (PFS) period of less than 8 months on RETi were classified as poor responders. We investigated the clinical patterns of disease progression (PD) and outcomes with subsequent therapies, evaluated by the overall response rate (ORR by investigator assessment) and PFS. PFS2 was calculated from RETi start to PD after subsequent line. Results: 173 pts from 32 centres were identified. Median age was 65, 61% were female, 41% were smokers, 81% had an ECOG performance status <2, 95% had adenocarcinoma, 18% had brain metastasis, 76% had RETi in first or second line. The administered RETi were selpercatinib in 55%, pralsertinib in 42%, other first generation RETi in 3% of pts. After a median follow up of 30.4 months (mo) (95%CI 26-32.1), 84 pts (48.6%) had PD after RETi, with a median PFS (mPFS) of 15.6 mo (95%CI 12.2-23.3) and an ORR of 72.2%. Radiological PD patterns included multisite PD in 46 (71%), oligoPD in 15 (23%), mixed response in 4 (6%). 7/15(47%) received local treatment while continuing RETi. Subsequent treatment line after RETi was administered in 37 pts (21%). Considering chemotherapy-based treatments, ORR and mPFS were 46% and 5.52 mo (4.07-11.3) overall, 57% and 4.53 mo (95%CI 1.4-NA) in 9 pts with chemo-immunotherapy, 27% and 5.88 mo (95%CI 2.1-NA) in 11 pts with platinum-doublet, 83% and 10.4 mo (8.28-NR) in 6 pts with bevacizumab plus chemotherapy (p=0.77 vs chemotherapy alone). Targeted therapy was administered in 8 patients: 6 received RETi after RETi (first generation) with 33% ORR and 3.83 mo (1.77-NR) mPFS, one patient had crizotinib plus RETi to target MET amplification found at resistance, with a PFS of 5.95 mo, one had alectinib alone, targeting SQSTM1-ALK fusion found at resistance, with PD after 1.58 mo. Cabozantinib was chosen for one pt, with a PFS of 5.52 mo and obtaining PR; one pt was treated with single-agent immunotherapy, with rapid PD after 1 month; one pt had an investigational antibody-drug conjugate, experiencing SD and a 4 mo PFS. PFS to subsequent treatment was not different between long and poor responders to RETi (13 and 15 pts,5.88 vs 4.53 m, respectively, p=0.75); PFS2 was longer in good responders to RETi (25 vs 16 mo,p=0.012). Conclusions: Disease progression to RETi most frequently involved multiple sites. Chemotherapy plus bevacizumab seemed to perform better than chemotherapy alone or chemo-immunotherapy. The benefit of tailored treatment basing on the molecular profile at PD needs to be further explored. Citation Format: Arianna Marinello, Wael Salem Zrafi, Giacomo Massa, Fabrizio Tabbò, Fabrizio Citarella, Filippo Gustavo Dall'Olio, Lindsay Colin, Emilio Bria, Giulio Metro, Josè Nicolas Minatta, Antonio Calles, Isabelle Monnet, Marco Tagliamento, Hortense Gaultier De Saint Basile, Nicolas Girard, Arianna Pagliaro, Diego Luigi Cortinovis, Judith Raimbourg, Carol Zanchetta, Giannis Mountzios, Frank Aboubakar Nana, Safae Terrisse, Alessandro Russo, Patricia Iranzo, Clarisse Audigier-Valette, Philippe Rochigneux, Vincent Fallet, Michael Duruisseaux, Sophie Cousin, Florian Guisier, Laura Mezquita, Jordi Remon, Anas Gazzah, David Planchard, Benjamin Besse, Mihaela Aldea. Clinical features of progression and outcomes with subsequent therapies in patients treated with RET-inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B145.

PD-1 Blockade before Autologous Stem Cell Transplantation Improves Outcomes in Relapsed/Refractory Classic Hodgkin Lymphoma: Results from a Multicenter Cohort

Introduction: Single arm studies incorporating PD-1 blockade and/or brentuximab vedotin (BV) to salvage regimen have produced encouraging results in transplant-eligible relapsed/refractory classic Hodgkin lymphoma (R/R cHL) and are increasingly used in practice. As prospective randomized studies comparing PD1 based salvage to other salvage regimens are lacking, we conducted a retrospective study comparing post-transplant outcomes of R/R cHL patients who received PD1-based regimen and other novel and conventional regimen. Methods: Consecutive adult patients with R/R cHL who received salvage therapy and underwent autologous stem cell transplant (ASCT) between 2010 and 2021 at 5 United States academic institutions were included. Demographics and clinical variables were recorded at relapse by electronic health records review. Study Objectives were post-ASCT progression free survival (PFS) and overall survival (OS). Results: 981 pts of R/R cHL were identified. At relapse, median age was 31 (IQR: 21-43) years, 504 (52%) were male, 323 (49%) had advanced stage, 353 (41%) had extranodal disease (END), 185 (22%) had B symptoms, 345 (45%) were refractory to frontline therapy and 317 (32%) relapsed within a year of frontline therapy.308 (31%) received >1 line of salvage before ASCT. Patients were divided into 3 groups based on salvage therapy received: 1) 195 (20%) patients received a PD-1 agent with or without BV at any point before ASCT (PD-1 group), 2) 312 (32%) patients received BV at any point before ASCT without PD-1 (BV group), and 3) 474 (48%) patients received no novel agent before ASCT (chemo group). PFS was significantly higher in PD1 group (2-yr PFS 93.1 (CI 95: 89.4-96.9)%); compared to BV (2 yr PFS 73.9 (CI 95: 69.1-79.1)% , p <0.0001) or chemo groups (2 yr PFS 71.6 (CI 95: 67.6-75.9)% , p<0.0001). PFS was not different between the BV and chemo groups (p=0.88) (Figure 1). OS was not significantly different between PD-1 group (2 yr OS 96.2 % (CI 95: 93.2-99.2), p=0.06), BV group (2 yr OS 94.3% (CI 95: 91.7-97.0), p=0.2) and chemo group (2 yr OS 91.8% (CI 95: 89.3-94.4)). Amongst pts who were transplanted in complete metabolic response (CMR), we assessed post-ASCT PFS and OS based on salvage therapy received immediately before ASCT. Pts who received PD-1 as last salvage therapy had improved PFS compared to chemo (HR: 0.15 (CI 95: 0.07-0.3), p= <0.0001) and BV (HR: 0.2 (CI 95: 0.08-0.5), p= <0.001). Pts receiving PD-1 immediately before ASCT also had higher OS compared to those receiving chemo (HR: 0.2 (CI 95: 0.05-0.8), p= 0.02) but not BV (HR: 0.8 (CI 95: 0.4-1.3), p=0.1). There was no difference between BV and chemo group in regards to PFS and OS. In multivariable analysis that included time to relapse, B symptoms, END, pre-ASCT response, number of salvage therapy lines before ASCT, year of transplant and BV consolidation, PD-1 salvage therapy had significantly higher PFS compared to chemotherapy (HR: 0.3 (CI 95: 0.2-0.5), p= <0.001). BV group had significantly lower PFS (HR: 3.34 (CI 95: 1.8-6.0), group=0.002) compared to PD1 group. PFS was not different between BV and chemo group (p= 0.7). OS was similar between all 3 groups. Similar PFS and OS were seen among patients receiving PD-1 + BV (n=83) and PD-1 with or without chemo (n =112) (p=0.96 for PFS; p= 0.72 for OS); as well as for patients receiving PD-1 as part of their first salvage therapy (n=151) or later salvage treatments (n=44) (p=0.45 for PFS, p= 0.3 for OS). Patients who received PD1 based regimen as last salvage therapy pre-ASCT had significantly better PFS (HR: 6.8 (CI 95: 2.4-19.2), p= <0.0001) and OS (HR: 10.6 (CI 95: 2.5-44.8), p= 0.0001) compared to patients who received PD1 prior to their last line of salvage therapy per-ASCT. Conclusion: Receipt of PD-1 based salvage therapy at any point before ASCT is associated with significantly improved PFS compared to either BV or chemotherapy-based salvage treatments. In the subgroup of patients transplanted in CMR, PD1 based last salvage regimen were associated with higher PFS compared to chemotherapy and BV and higher OS compared to chemotherapy. PD1 based last salvage therapy pre-ASCT was associated with better survival compared to PD1 prior to last salvage therapy. Results of this study strongly support the use of PD-1 based salvage therapy for patients with R/R cHL. S.D., R.M., H.S contributed equally. R.S., M.M. contributed equally.

Bibliometric analysis of the global scientific production on machine learning applied to different cancer types

Cancer disease is one of the main causes of death in the world, with million annual cases in the last decades. The need to find a cure has stimulated the search for efficient treatments and diagnostic procedures. One of the most promising tools that has emerged against cancer in recent years is machine learning (ML), which has raised a huge number of scientific papers published in a relatively short period of time. The present study analyzes global scientific production on ML applied to the most relevant cancer types through various bibliometric indicators. We find that over 30,000 studies have been published so far and observe that cancers with the highest number of published studies using ML (breast, lung, and colon cancer) are those with the highest incidence, being the USA and China the main scientific producers on the subject. Interestingly, the role of China and Japan in stomach cancer is correlated with the number of cases of this cancer type in Asia (78% of the worldwide cases). Knowing the countries and institutions that most study each area can be of great help for improving international collaborations between research groups and countries. Our analysis shows that medical and computer science journals lead the number of publications on the subject and could be useful for researchers in the field. Finally, keyword co-occurrence analysis suggests that ML-cancer research trends are focused not only on the use of ML as an effective diagnostic method, but also for the improvement of radiotherapy- and chemotherapy-based treatments.

Baseline mutations and ctDNA dynamics as prognostic and predictive factors in ER-positive/HER2-negative metastatic breast cancer patients.

Prognostic and predictive biomarkers to CDK4/6 inhibitors are lacking. Circulating tumour DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy. Correlative blood samples were collected at baseline (C1D1) and prior to treatment (C1D15). Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A pre-specified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model. 201 patients were profiled at baseline, with ctDNA detection associated with worse PFS/OS. Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n=120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms. We show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with HR+/HER2- MBC harbouring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted.

Nanozymes with Peroxidase-like Activity for Ferroptosis-Driven Biocatalytic Nanotherapeutics of Glioblastoma Cancer: 2D and 3D Spheroids Models.

Glioblastoma (GBM) is the most common primary brain cancer in adults. Despite the remarkable advancements in recent years in the realm of cancer diagnosis and therapy, regrettably, GBM remains the most lethal form of brain cancer. In this view, the fascinating area of nanotechnology has emerged as an innovative strategy for developing novel nanomaterials for cancer nanomedicine, such as artificial enzymes, termed nanozymes, with intrinsic enzyme-like activities. Therefore, this study reports for the first time the design, synthesis, and extensive characterization of innovative colloidal nanostructures made of cobalt-doped iron oxide nanoparticles chemically stabilized by a carboxymethylcellulose capping ligand (i.e., Co-MION), creating a peroxidase-like (POD) nanozyme for biocatalytically killing GBM cancer cells. These nanoconjugates were produced using a strictly green aqueous process under mild conditions to create non-toxic bioengineered nanotherapeutics against GBM cells. The nanozyme (Co-MION) showed a magnetite inorganic crystalline core with a uniform spherical morphology (diameter, 2R = 6-7 nm) stabilized by the CMC biopolymer, producing a hydrodynamic diameter (HD) of 41-52 nm and a negatively charged surface (ZP~-50 mV). Thus, we created supramolecular water-dispersible colloidal nanostructures composed of an inorganic core (Cox-MION) and a surrounding biopolymer shell (CMC). The nanozymes confirmed the cytotoxicity evaluated by an MTT bioassay using a 2D culture in vitro of U87 brain cancer cells, which was concentration-dependent and boosted by increasing the cobalt-doping content in the nanosystems. Additionally, the results confirmed that the lethality of U87 brain cancer cells was predominantly caused by the production of toxic cell-damaging reactive oxygen species (ROS) through the in situ generation of hydroxyl radicals (·OH) by the peroxidase-like activity displayed by nanozymes. Thus, the nanozymes induced apoptosis (i.e., programmed cell death) and ferroptosis (i.e., lipid peroxidation) pathways by intracellular biocatalytic enzyme-like activity. More importantly, based on the 3D spheroids model, these nanozymes inhibited tumor growth and remarkably reduced the malignant tumor volume after the nanotherapeutic treatment (ΔV~40%). The kinetics of the anticancer activity of these novel nanotherapeutic agents decreased with the time of incubation of the GBM 3D models, indicating a similar trend commonly observed in tumor microenvironments (TMEs). Furthermore, the results demonstrated that the 2D in vitro model overestimated the relative efficiency of the anticancer agents (i.e., nanozymes and the DOX drug) compared to the 3D spheroid models. These findings are notable as they evidenced that the 3D spheroid model resembles more precisely the TME of "real" brain cancer tumors in patients than 2D cell cultures. Thus, based on our groundwork, 3D tumor spheroid models might be able to offer transitional systems between conventional 2D cell cultures and complex biological in vivo models for evaluating anticancer agents more precisely. These nanotherapeutics offer a wide avenue of opportunities to develop innovative nanomedicines for fighting against cancerous tumors and reducing the frequency of severe side effects in conventionally applied chemotherapy-based treatments.

Abstract 1689: The role of circular RNAs in triple negative breast cancer and chemotherapy resistance

Abstract Background: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among women worldwide. Triple negative breast cancer (TNBC) represents 15-20% of all breast cancers and is an aggressive subtype. Chemotherapy-based treatments remain the standard of care for TNBC. Unfortunately, chemotherapy resistance is common, and for these patients, outcomes are poor and alternative treatment strategies remain an unmet need. circRNAs are a newly identified class of noncoding RNA molecules with covalently closed circular structures. An increasing number of recent studies including ours have indicated that circRNAs play crucial roles in regulating tumor development and chemoresistance. However, the role of circRNAs in the process of chemotherapy resistance and TNBC progression is not clear. Materials and Methods: As a first step towards identifying circRNAs that participate in the development of chemoresistance in TNBC cells, and to determine if targeting such circRNAs is a novel and efficacious therapeutic strategy, doxorubicin-resistant (Doxo-R), paclitaxel-resistant (PTX-R), and double-resistant (DP-R) cell lines were generated from MDA-MB-231. Human circRNA microarrays were utilized to profile the expression of approximately 14,000 known circRNAs in normal breast tissue, matched patient-derived xenografts (PDX) generated prior to and following neoadjuvant chemotherapy (NAC), and TNBC chemosensitive and chemoresistant cell lines. Top hits were validated using RT-PCR. Results: circRNA microarray profiling identified 429 and 310 transcripts differentially expressed in doxorubicin and paclitaxel resistant cells, respectively, compared to parental chemosensitive cell lines (|FC| ≥ 1.5; p value < 0.05). In comparison to pre-NAC derived xenografts, 1,396 circRNAs were dysregulated among post-NAC PDX models. Further, three circRNAs (hsa_circ_001388, hsa_circ_104652, and hsa_circ_061260) were upregulated in Doxo-R, PTX-R, and post-NAC PDX samples compared to their respective controls. Among these three circRNAs, hsa_circ_001388 (also known as circNSD2) was the only transcript also predicted to be translated into a novel and uncharacterized protein given the presence of a high confidence translation initiation site and IRES sequence. Ongoing studies are aimed at determining the role of circNSD2 protein in breast cancer carcinogenesis, progression, and response to standard of care chemotherapeutics and the mechanistic process by which this protein functions. Additionally, the efficacy of specifically targeting this circRNA as a novel therapeutic approach is being explored. Conclusions: Increasing knowledge of the important functions of circRNAs underlying drug resistance will provide new opportunities for developing efficacious therapeutic strategies and prognostic/predictive biomarkers for TNBC. Citation Format: Xiyin Wang, Michael J. Emch, Xiaojia Tang, Jia Yu, Krishna R. Kalari, Liewei Wang, Matthew P. Goetz, John R. Hawse. The role of circular RNAs in triple negative breast cancer and chemotherapy resistance [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 1689.

Abstract PD18-07: Omission of chemotherapy in the treatment of HER2-positive and hormone-receptor positive metastatic breast cancer – interim results from the randomized phase 3 DETECT V trial

Abstract Background: Metastatic breast cancer (MBC) is an incurable disease and both the improvement of survival and maintenance of quality of life (QoL) are equally important aims of treatment planning. In patients with HER2-positive MBC, taxane-based chemotherapy in combination with dual HER2 targeted therapy with trastuzumab (T) and pertuzumab (P) is the standard of care first line therapy. However, adverse events are well-known side effects of any cytostatic treatment and can seriously impact the patients’ QoL. In addition, in HER2-positive MBC activated estrogen receptor (ER) signaling is associated with primary or secondary resistance. Thus, for patients with HER2-positive and hormone-receptor (HR) positive MBC, the synergistic combination of dual HER2-targeted therapy plus endocrine therapy might offer a better treatment option compared to cytotoxic chemotherapy-based treatments. Methods: Between 9/2015 and 11/2022, the multicenter phase III DETECT V trial randomized patients with HER2-positive and HR-positive (i.e. ER positive and/or progesterone-receptor positive) MBC in the 1st-3rd line setting 1:1 to receive T and P combined with either endocrine therapy or chemotherapy followed by maintenance therapy with T, P and endocrine therapy. Chemotherapy and the endocrine agents could be chosen from a variety of available regimens according to physicians’ choice. Based on emerging data strongly suggesting an additional benefit of CDK4/6 inhibitors, an amendment came into effect in January 2019 with the addition of ribociclib to both treatment arms after 124 patients had been randomized. The primary objective of DETECT V is to compare tolerability between the chemotherapy-free and chemotherapy-containing treatment arm; secondary objectives comprise the comparison of PFS, OS and safety. Here we report results of an unplanned interim analysis with data cut off June 22th 2022. Results: The results reported here are based on 153 patients for whom end of study was documented at the time of data cut off for this interim analysis (120 patients randomized before and 33 patients randomized after the addition of ribociclib; 115 patients in the 1st line setting; 77 and 76 patients in the chemotherapy-free and chemotherapy-containing arm, respectively). Overall survival (OS) and progression-free survival (PFS) did not differ between patients receiving chemotherapy-free and chemotherapy-containing treatment (median OS not yet reached vs. 37.2 months, hazard ratio 0.87, 95% CI 0.51 – 1.50, p = 0.63; median PFS 15.6 vs. 14.9 months, hazard ratio 0.98, 95% CI 0.64 – 1.52, p = 0.93). Study treatment was terminated prematurely significantly less often in the chemotherapy-free treatment arm (43.9% vs. 72.2%, p = 0.001). Furthermore, tolerability was better for the chemotherapy-free treatment as there were less adverse events (AEs) of any grade (585 vs. 793; 70 vs. 71 patients affected), less AEs grade 3 or higher (66 vs. 90; 33 vs. 48 patients affected) and less serious adverse events (45 vs. 52; 28 vs. 29 patients affected) reported in the chemotherapy-free treatment arm as compared to the chemotherapy-containing treatment arm. Conclusion: These preliminary results suggest that chemotherapy-free treatment for patients with triple-positive MBC might be an effective and well tolerated option. Citation Format: Wolfgang Janni, Tanja Fehm, Volkmar Müller, Fabienne Schochter, Amelie De Gregorio, Thomas Decker, Andreas Hartkopf, Marianne Just, Jacqueline Sagasser, Marcus Schmidt, Pauline Wimberger, Maggie Banys-Paluchowski, Peter A. Fasching, Brigitte Rack, Sabine Riethdorf, Andreas Schneeweiss, Diethelm Wallwiener, Franziska Meier-Stiegen, Natalia Krawczyk, Oliver Hoffmann, Jens-Uwe Blohmer, Dieter Niederacher, Hans Neubauer, Klaus Pantel, Thomas W. Friedl, Jens Huober. Omission of chemotherapy in the treatment of HER2-positive and hormone-receptor positive metastatic breast cancer – interim results from the randomized phase 3 DETECT V trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-07.

OUTCOMES OF SECOND-LINE TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): RETROSPECTIVE ANALYSIS OF THE BRAZILIAN REGISTRY OF CLL

Real-world data from low and middle-income countries on the management of chronic lymphocytic leukemia (CLL) is needed to understand current clinical practices and unmet needs. Delayed or unequal access to novel agents may negatively impact disease outcomes in (RR) CLL. To describe clinical outcomes of second-line treatment in patients with CLL included in the Brazilian Registry of CLL (BRCLL). Observational study of second-line CLL treatments started between 2006 and 2021. BRCLL is a prospective non-interventional data collection tool. All participant centers registered their CLL patients online, after study approval at each center's ethical review board. Second-line treatments for 444 CLL patients were included. Median age at start of second-line treatment was 66 years (range: 23-93), and 264 were male (59%). Binet staging at CLL was A in 139 patients (36%), B in 139 (36%), and C in 107 (28%). Unmutated IGHV was observed in 61% of patients and FISH was performed in 166 patients (37%), of which 33 patients had del(17p) (20%). The most commonly prescribed regimens were: FC (+/- R) in 160 patients (36%); chlorambucil (+/- R) in 109 (25%); ibrutinib in 63 (14%); CHOP/CVP (+/- R) in 62 (14%); monoclonal antibodies (+/- steroids) in 33 (7%); allogeneic stem cell transplantation in 9 (2%) and venetoclax in 8 (2%). Forty patients (9%) were treated in clinical trials. Median follow-up after second-line treatment was 34 months (range: 3-176). Median time-to-next treatment (TTNT) was 28 months. TTNT was statistically longer in patients who received second-line with ibrutinib or venetoclax in comparison with FC or chlorambucil +/- anti-CD20 (not reached versus 29 months, p < 0.0001) or those who received other regimens (CHOP or CVP +/- anti-CD20, monoclonal antibodies +/- steroids – 12 months, p < 0.0001). Higher 3-year treatment-free survival (TFS) was also observed with ibrutinib or venetoclax (69% versus 41% and 23%, respectively, p < 0.0001). Among patients included in clinical trials, 3-year TFS was also higher (70% versus 38%, p < 0.0001). TFS for patients receiving allogeneic stem cell transplantation was 86% at 3 years. Overall survival (OS) probability at 3 years was 71%. OS was significantly shorter in those who received other regimens (CHOP/CVP-like or monoclonal antibodies +/- steroids; 53%), in comparison with those who received ibrutinib or venetoclax (80%, p < 0.0001), or FC/chlorambucil-based chemotherapy (69%, p = 0.01). Chemotherapy-based second-line CLL treatments were frequent over the reported period, with inferior outcomes for CHOP/CVP-like treatments and monoclonal antibodies with or without steroids. Considering the approval of Bruton tyrosine kinase and BCL2 inhibitors in recent years, a shift towards targeted agents in RR CLL is anticipated, but cannot be established at this time for the majority of patients in second line reported to the BRCLL. While the adoption of targeted therapies was associated with longer TTNT and OS, access to these agents is still very limited in our setting.

ZNF204P is a stemness-associated oncogenic long non-coding RNA in hepatocellular carcinoma

Hepatocellular carcinoma is a major health burden, and though various treatments through much research are available, difficulties in early diagnosis and drug resistance to chemotherapy-based treatments render several ineffective. Cancer stem cell model has been used to explain formation of heterogeneous cell population within tumor mass, which is one of the underlying causes of high recurrence rate and acquired chemoresistance, highlighting the importance of CSC identification and understanding the molecular mechanisms of CSC drivers. Extracellular CSC-markers such as CD133, CD90 and EpCAM have been used successfully in CSC isolation, but studies have indicated that increasingly complex combinations are required for accurate identification. Pseudogene-derived long non-coding RNAs are useful candidates as intracellular CSC markers - factors that regulate pluripotency and self-renewal – given their cancer-specific expression and versatile regulation across several levels. Here, we present the use of microarray data to identify stemness-associated factors in liver cancer, and selection of sole pseudogene-derived lncRNA ZNF204P for experimental validation. ZNF204P knockdown impairs cell proliferation and migration/invasion. As the cytosolic ZNF204P shares miRNA binding sites with OCT4 and SOX2, well-known drivers of pluripotency and self-renewal, we propose that ZNF204P promotes tumorigenesis through the miRNA-145-5p/OCT4, SOX2 axis.

Real-World Multiple Myeloma Treatment Patterns By Patient Characteristics and Outcomes in the United States

Introduction: Despite numerous therapies approved for multiple myeloma (MM) in the past decade, the disease remains largely incurable. As a result, patients (pts) typically require successive lines of therapy, comprised of various combinations of drugs, to treat relapsed disease. As the treatment landscape evolves, continued real-world (RW) studies provide additional understanding of the treatment patterns of MM pts outside of clinical trials, particularly for those with unmet medical need and/or high-risk disease. In this retrospective, observational cohort study, we examined RW treatment patterns among MM pts overall and within patient subgroups classified by age, race/ethnicity, renal impairment (RI), cytogenetic risk, and 1q21 amplification, as well as patient outcomes.Methods: This study used the nationwide Flatiron Health electronic health record-derived de-identified database of MM pts treated in the United States. During the study period, January 1, 2016 to April 30, 2021, pts who had ≥1 line of therapy or whose first-line treatment was initiated after the study start were included. Treatment class regimens (lines 1-4) were classified as: proteasome inhibitor (PI)-based, immunomodulatory drug (IMiD)-based, PI + IMiD-based, chemotherapy-based, antibody-based, or other treatments. We examined patient characteristics as well as treatment patterns overall and in patient subgroups. We also assessed real-world progression-free survival (rwPFS), defined as the time from start of line therapy to the date of progression or death, by treatment regimen received.Results: At the time of data cutoff, 5465 pts received ≥1 line of therapy; 45.3% of pts were female, 57.4% were white, median age at the start of first-line therapy was 70 years (interquartile range 62-77), and 88.7% received care at community practices. A total of 14.6% had high-risk cytogenetic abnormalities, 21.0% had 1q21 amplification, 20.7% had International Staging System stage III at diagnosis and 33.2% had RI (eGFR <60 mL/min/1.73 m 2) at the start of first-line therapy. The most common first-line regimens were PI + IMiD-based (53.4%), whereas 12.8% received PI-based, 11.5% IMiD-based, 13.4% chemotherapy-based, 2.8% antibody-based, and 6.1% had other treatments (Figure 1). Although uncommon in first-line therapy, antibody-based treatments were more commonly used in later lines of therapy (second-line: 21.0%; third-line: 33.7%; fourth-line: 40.0%). In first-line, pts aged ≥75 years were less likely to receive PI + IMiD-based regimens than those aged <75 years (40.4% vs 60.1%) (Figure 2). Similarly, RI pts received PI + IMiD-based regimens less frequently in first-line than those without impairment (47.8% vs 65.0%). In first-line, 18.9% of pts had evidence of undergoing a transplant. Both older pts and those with RI were also less likely to receive a transplant as part of their first-line treatment (1.7% vs 27.7% and 13.9% vs 24.2% respectively). Treatment differences were less pronounced in later lines as well as by race/ethnicity, cytogenetic risk, and 1q21 amplification. In first-line therapy, rwPFS was longer for pts treated with PI + IMiD-based regimens (median [95% confidence interval], 29.5 months [27.3-31.9]). In later lines of therapy, pts treated with IMiD-based regimens had longer median rwPFS (second-line: 22.7 months [18.5-30.4]; third-line: 19.7 months [14.2-37.0]; fourth-line: 16.1 months [6.4-26.7]). Additional analyses examining newer treatment regimens will be presented.Conclusions: PI + IMiD combination therapy was the most common first-line therapy. Although not commonly used in first-line therapy, antibody-based regimens are increasingly used in later lines of therapy. Older pts as well as pts with RI were less likely to receive PI + IMiD regimens or transplant in first-line therapy. Pts receiving PI + IMiD regimens in first-line therapy had longer rwPFS. Pts receiving IMiD-based regimens had longer rwPFS in later lines. Analyses of newer treatment regimens to be presented within this dataset will provide additional insight into changes in RW treatment patterns in the era of novel agents. [Display omitted] DisclosuresRichter: BMS, Karyopharm, Antengene: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Speakers Bureau; Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai: Current Employment. Singh: Sanofi: Current Employment. Rice: Sanofi: Current Employment, Current holder of individual stocks in a privately-held company.

The evolving role of precision medicine in the management of advanced sarcomas – A mini review

Sarcomas are a heterogenous group of cancers, traditionally with dismal outcomes. They were initially treated with histology agnostic chemotherapy-based regimens usually centered around anthracyclines. With the availability of molecular diagnostics especially next-generation sequencing, the advanced genomics of sarcomas was slowly unveiled. Precision medicine not only enables a better diagnosis in sarcomas but also allows in identifying better targets for treatment of sarcoma subtypes. GENSARC study proved that using correct molecular diagnostics, enabled in a better diagnosis and treatment of soft tissue sarcomas (STSs). Notable examples of targeted therapies with great success in sarcomas include imatinib and other tyrosine kinase inhibitors in gastrointestinal stromal tumors, neurotrophic tyrosine receptor kinase inhibitors infantile fibrosarcoma, and crizotinib in inflammatory myofibroblastic tumors. Thus, treatment of sarcomas has been gradually changing from traditional chemotherapy-based treatments to the modern targeted therapy. In this review, we hope to impress on the evolving role of precision medicine in sarcoma subtypes especially STS.

Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC).

e15016 Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4. Capecitabine (X) at optimal dose of 7 days on and 7 days off schedule (7/7) is well-tolerated with low rates of ≥ grade (G3) diarrhea. Methods: We conducted phase Ib/II study of N with X (7/7) with loperamide and colestipol prophylaxis in patients (pts) with pretreated HER2+ MBC (NCT03377387). Eligible pts had normal left ventricular ejection fraction (≥ 50%), any and &lt; 4 prior chemotherapy-based treatments in phase Ib and II, respectively. Primary endpoint of phase Ib is maximum tolerated dose (MTD) and phase II is response rate. Secondary endpoints are safety, tolerability, and progression-free survival. Exploratory endpoint is to quantify cell-free DNA (cfDNA), correlating with response. Phase Ib follows traditional 3+3 design with 4 dose levels. In phase II, if &gt; 3/9 respond, study is expanded to 24. If &gt; 10/24 respond, study is deemed successful. Results: As of 2-4-2021, 10 pts were enrolled in phase Ib. 4 pts were treated at dose level 1 (X at 1500 mg BID at 7/7 and N at 240 mg daily); 2/4 pts experienced with G3 diarrhea during cycle 1. Six pts were treated at dose level -1 (X at 1000 mg BID 7/7 and N at 240 mg daily); 1 (17%) developed G3 diarrhea. The MTD is X at 1000 mg BID 7/7 and N at 240 mg daily. Twenty-two of 24 pts have been enrolled in phase II. Of 22 pts, data show 6 with partial response, 8 with stable disease, 3 with progressive disease, and 5 have not been assessed radiographically. Overall, 6/22 (27.3%) and 1/22 (4.5%) had all G and G3 diarrhea, respectively. Other significant toxicities at MTD included G2 hand foot syndrome (n = 1, 4.5%), G1 fatigue (n = 1, 4.5%) and G1 nausea (n = 4, 18%). Conclusions: The MTD is X at 1000 mg BID at 7/7 and N at 240 mg daily. This combination is safe and well tolerated with G3 diarrhea rate of 4.5%, which is significantly lower than the X 14/7 schedule in NALA study. The phase II portion of the study is near completion and updated result will be presented. Analysis of cfDNA, to correlate with response for phase II portion, is ongoing. Clinical trial information: NCT03377387.

Resistance to Cell Death in Mucinous Colorectal Cancer-A Review.

Simple SummaryMucinous colorectal cancer is characterised by abundant mucin glycoprotein production and is associated with resistance to chemotherapy-based treatments. This review outlines mechanisms for cell death resistance present in mucinous colorectal cancer including glycoprotein interactions with cell survival and cell apoptotic pathways. Further mechanisms are explored, including alterations in the expression of chemotherapy metabolism and resistance genes. This review identifies directions for future investigation of mucinous colorectal cancer and novel treatment strategies.Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10–15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is frequently associated with resistance to apoptosis. Inferior prognosis is observed in mucinous CRC, particularly in rectal cancer and metastatic cases. Mucins are heavily glycosylated secretory or transmembrane proteins that participate in protection of the colonic epithelium. MUC2 overexpression is a hallmark of mucinous CRCs. Mucinous CRC is associated with KRAS and BRAF mutation, microsatellite instability and the CpG island methylator phenotype. Mutations of the APC gene and p53 mutations which are characteristic non-mucinous colorectal adenocarcinoma are less common in mucinous CRC. Both physical and anti-apoptotic properties of mucin provide mechanisms for resistance to cell death. Mucin glycoproteins are associated with decreased expression of pro-apoptotic proteins, increased expression of anti-apoptotic proteins and increased cell survival signaling. The role for BCL-2 proteins, including BCL-XL, in preventing apoptosis in mucinous CRC has been explored to a limited extent. Additional mechanisms opposing cell death include altered death receptor expression and altered mutation rates in genes responsible for chemotherapy resistance. The roles of alternate cell death programs including necroptosis and pyroptosis are not well understood in mucinous CRC. While the presence of MUC2 is associated with an immunosuppressive environment, the tumor immune environment of mucinous CRC and the role of immune-mediated tumor cell death likewise require further investigation. Improved understanding of cell death mechanisms in mucinous CRC may allow modification of currently used regimens and facilitate targeted treatment.

Recent Advancements in Stimuli Responsive Drug Delivery Platforms for Active and Passive Cancer Targeting.

Simple SummaryCancer is one of the leading causes of death globally. Several studies, efforts and treatment strategies have been put forth for the treatment of different types of cancers. Several chemotherapeutic agents have been discovered and utilized for the treatment of various types of cancers and tumors, which play an important role in improving the quality of life of patients. The key problems associated with the abovementioned chemotherapeutic agents are the limited target ability and non-selective toxicity. The current review focuses on the achievement of improved targeting of anticancer agents at the tumor microenvironment without affecting normal tissues. The fulfilment of the mentioned objectives by stimuli-responsive drug delivery systems, as physical stimuli-responsive drug delivery systems and chemical stimuli-responsive drug delivery systems through active and passive targeting have extensively been discussed in the current review. The current review will help the wide community of researchers conducting research in targeted drug delivery systems and anticancer treatment strategies.The tumor-specific targeting of chemotherapeutic agents for specific necrosis of cancer cells without affecting the normal cells poses a great challenge for researchers and scientists. Though extensive research has been carried out to investigate chemotherapy-based targeted drug delivery, the identification of the most promising strategy capable of bypassing non-specific cytotoxicity is still a major concern. Recent advancements in the arena of onco-targeted therapies have enabled safe and effective tumor-specific localization through stimuli-responsive drug delivery systems. Owing to their promising characteristic features, stimuli-responsive drug delivery platforms have revolutionized the chemotherapy-based treatments with added benefits of enhanced bioavailability and selective cytotoxicity of cancer cells compared to the conventional modalities. The insensitivity of stimuli-responsive drug delivery platforms when exposed to normal cells prevents the release of cytotoxic drugs into the normal cells and therefore alleviates the off-target events associated with chemotherapy. Contrastingly, they showed amplified sensitivity and triggered release of chemotherapeutic payload when internalized into the tumor microenvironment causing maximum cytotoxic responses and the induction of cancer cell necrosis. This review focuses on the physical stimuli-responsive drug delivery systems and chemical stimuli-responsive drug delivery systems for triggered cancer chemotherapy through active and/or passive targeting. Moreover, the review also provided a brief insight into the molecular dynamic simulations associated with stimuli-based tumor targeting.

LncRNA BANCR Attenuates the Killing Capacity of Cisplatin on Gastric Cancer Cell Through the ERK1/2 Pathway.

PurposeChemotherapy-based comprehensive treatments are the most important therapeutic methods for patients with advanced gastric cancer, but chemoresistance often cause treatment failure. Long non-coding RNA (LncRNA) BRAF-activated non-coding RNA (BANCR) has been shown to participate in many biological behaviors of multiple cancers. However, the biological roles of LncRNA BANCR in chemoresistance of gastric cancer remain unclear. Here, we aimed to evaluate the functions of LncRNA BANCR on the therapy of gastric cancer.MethodsIn this study, LncRNA BANCR expression was detected in gastric cancer patient samples and cell lines by quantity polymerase chain reaction (qPCR). Cell proliferation and viability in cisplatin-treated cells were measured using clonogenic survival assay and cell counting kit-8. The levels of ERK1/2 pathway molecules were tested with Western blot. Ly3214996, an inhibitor of ERK signal pathway, was administered to assess the effects of BANCR overexpression on gastric cancer cell with cisplatin-treated resistance. Moreover, the role of BANCR in cisplatin resistance of gastric cancer was validated in xenograft mouse models in vivo.ResultsOur study revealed that LncRNA BANCR expression was also significantly increased in gastric cancer tissues compared with adjacent normal tissues. Furthermore, we found that BANCR overexpression promoted gastric cancer cell resistance to cisplatin in vitro. Ly3214996 treatment abolished the BANCR overexpression-mediated gastric cancer cell cisplatin resistance via regulating the phosphorylation of ERK protein. Knock-down of BANCR significantly delayed tumor growth in xenograft mouse models.ConclusionBANCR promoted cisplatin resistance of gastric cancer cells by activating ERK1/2 pathway. Inhibition of BANCR markedly suppressed the growth of gastric cancer cells in vitro as well as in vivo. These results provided a new strategy for gastric cancer therapy via targeting BANCR.

Treatments for combined small cell lung cancer patients.

BackgroundCombined small cell lung cancer (CSCLC) is a subtype of small cell lung cancer (SCLC) which contains both components of SCLC and non-small cell lung cancer (NSCLC). The prognostic outcomes and treatment strategy of it are still unclear. A large-scale retrospective study was performed to investigate proper treatments for CSCLC.MethodsAll cases of CSCLC were identified from the SEER database during the period of 2004–2016. Clinical characteristics, first-line treatments, surgical procedures and survival data including overall survival (OS) and cancer-specific survival (CSS) were analyzed.ResultsA total of 37,639 SCLC patients were identified. CSCLC accounted for 2.1% (784/37,639). The mean age of CSCLC cohort is 67.3±9.9 years old. Male and white ethnicity patients were accounted for larger proportions (55.7% and 80.4%). The oncological characteristics of CSCLC were consistent with SCLC that most of patients were diagnosed as higher grade and advanced stages. The prognosis of CSCLC was better than SCLC but worse than NSCLC in IA-IIIA stages. No difference was observed in IIIB-IV. Surgery was beneficial in IA-IB stage CSCLC. Adjuvant chemotherapy seemed to have few effects on early stage patients. Trimodality treatment could significantly improve OS in IIA-IIIA CSCLC patients. Chemotherapy-based treatment is predominant choice in advanced stage patients.ConclusionsCSCLC is a rare and special subtype of SCLC. It has better survival outcome than non-CSCLC in early stage. Surgical treatment is crucial in early stage of CSCLC. Prognostic improvement might be achieved from trimodality treatment in stage IIA-IIIA. Chemotherapy-based treatments should be considered in advanced stage. The effect of surgical treatments in advanced stage patients should be further investigated.

Abstract PO-021: Impact of COVID-19 in continuity of cancer treatment for lung cancer patients

Abstract Background: We aimed to analyze the impact on treatment delivery in patients with lung cancer during the COVID-19 pandemic and to describe the patterns of treatment change. Methods: We accessed treatment records of all lung cancer patients treated from 02/20 to 06/20 at the oncology day hospital in our institution (HGUGM; Madrid, Spain). We have prospectively identified all COVID-19 lung cancer patients confirmed by SARS-CoV-2 RT-PCR and included all those on active treatment (&amp;lt;30 days from last dose of any systemic therapy). Results: A total of 242 patients with lung cancer were receiving active treatment as follows: chemotherapy (117 pts, 48%), immunotherapy (56 pts, 23%), targeted therapy (52 pts, 21%), chemo-immunotherapy (13 pts, 5%), radio-immuno-chemotherapy (4 pts, 2%). Intention of treatment was palliative in 84% vs. curative in 16% (28 pts on chemoradiation; 11 pts on adjuvant/neoadjuvant therapy). Median number of treatment lines was 1 (range 1-6). 11 patients had confirmed COVID-19 illness during active cancer treatment, and 5 patients died due to COVID-19. On average, 61 patients with lung cancer were treated per week before the pandemic. After an initial peak during the first week of pandemic, treatment delivery dropped by -62.2% four weeks after the first case confirmed in our institution (chemotherapy, -58.2%; immunotherapy, -72.6%; chemo-immunotherapy, -100.0%; targeted therapy, -59.0%) and came back to normal at week +7. Treatment interruption or dose delay was observed in 125 pts (28% temporal, 24% definitive). Overall, 23 patients refused to continue treatment due to fear or mobility restrictions due to the pandemic. Additionally, we identified doses skipped in 51 pts (21%), increase on dose intervals in 42 pts (17%), and dose reductions in 16 pts (7%). Route of administration remained the same for all pts but 1 (i.v. to oral). Although absolute use of G-CSF fell by -57.9% during the pandemic, tied to less administration of chemotherapy, the relative use of G-CSF increased in patients receiving chemotherapy-based treatments: G-CSF was initiated in 31 pts who were not previously receiving G-CSF, and expanded in days of use in 7 pts already on treatment. Telemedicine was used in 106/242 patients (44%) to minimize physical presence in the hospital. Drug home delivery system was initiated in 22 patients (9% of total), all of them on targeted therapy (representing 42% of all active patients on targeted therapy). Of the 32 patients who were receiving treatment in clinical trials (10 pts immunotherapy; 8 pts targeted therapy; 8 pts chemo-immunotherapy; 2 chemotherapy, 4 radio-chemo-immunotherapy), neither treatment delays nor COVID-19 illness was documented in any patient. Conclusions: COVID-19 pandemic significantly modified treatment patterns in patients with lung cancer who were receiving active treatment. Measures were taken to reduce the number of visits to outpatient facilities, and treatment home delivery was facilitated when feasible. Citation Format: Antonio Calles, Manuel Alva, Inmaculada Aparicio, Javier Soto, Natalia Gutierrez, Marianela Bringas, Vicente Escudero, Roberto Collado, Mar Galera, Rosa Alvarez. Impact of COVID-19 in continuity of cancer treatment for lung cancer patients [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-021.

AVM0703 as a novel stand alone or combination therapy for lymphoma.

42 Background: Chemotherapy remains a vital part of cancer treatment. There is an urgent need to reduce the toxicities associated with chemotherapy-based treatments especially in the pediatric and young adult population where the risk for chemo-induced secondary cancers is high. AVM0703 is a new treatment option that can be used as a stand-alone or in combination with chemo for relapsed/refractory lymphoma patients. AVM0703 is effective at lymphoablating while sparing red blood cells, platelets, and hematopoietic stem cells. AVM0703 is a novel patent-pending formulation of a repurposed drug without the toxic excipients unlike existing formulations. AVM0703 has anti-tumor activity in an immunocompetent mouse model of B-cell lymphoma (A20) as both a stand-alone treatment and in combinations with current therapeutics. Methods: Wild-type BALB/c mice were implanted with A20 tumor cells suspended in a 50% Matrigel mixture and implanted subcutaneously. Palpable tumors were visible within seven days. Mice were dosed with either high-dose AVM0703 alone, or in combination with intraperitoneal cyclophosphamide and fludarabine. Mice were then monitored for tumor growth and changes in body weight. Results: Mice dosed repeatedly with AVM0703 survived 20 days longer than mice dosed with placebo and displayed no significant toxicity or body weight loss. In a separate study, mice treated with 2 doses of Cy/Flu had a loss of tumors similar to 1 dose of AVM0703 + 1 dose of Cy/Flu. Additionally, when compared to standard treatments like CHOP, in the same A20 lymphoma model, the AVM0703 + Cy/Flu combination had better tumor efficacy than 2 cycles of CHOP. Unlike 2XCHOP treatment, which induced greater than 30% body weight loss and death of 18% of the mice due to drug toxicity, the AVM0703 + Cy/flu combination had no observed toxicity or body weight loss. Conclusions: AVM0703 can reduce the number of chemotherapy cycles without affecting efficacy and decrease the toxicities associated with chemo and will help to provide a better quality of life for patients.