Abstract
Introduction: Monoclonal antibodies against the Epidermal Growth Factor Receptor (EGFR) such as cetuximab or panitumumab are used for the treatment of metastatic colorectal cancer (mCRC) ...patients. Unfortunately, most patients develop resistance against these therapies within months. Several studies have shown that aberrations in the RAS pathway are responsible for resistance. However, even in metastases that are refractory to anti-EGFR treatment a significant fraction of RAS wild-type (wt) cells remain. These findings suggest a cross-talk between RAS mutant and wt cells in mediating resistance in the wt compartment.
Methods: Mouse and patient-derived organoids from mCRC as well as CRC cell lines were used to test the contribution of extracellular vesicles in mediating resistance in RAS wt cells. Using conditioned media, transfection experiments and liquid biopsies (plasma and urine) from patients differential expression of the let-7g microRNA was demonstrated in microvesicles from cetuximab sensitive and resistant cells. Changes in expression of let-7g were further analyzed by in-situ hybridization in tissues.
Results: Conditioned media from RAS mutant organoids rendered RAS wt organoids resistant against cetuximab treatment. Basal let-7g expression from pre-treatment plasma and urine samples of RAS wt patients correlated with clinical outcome and changes in let-7g circulating levels mirrored clinical behavior. In-situ hybridization in tissues confirmed changes in expression of the let-7g microRNA observed in plasma and urine samples.
Conclusions: Our data suggest that let-7g microRNA might function as a paracrine mediator of anti-EGFR resistance and might be exploited as a non-invasive biomarker of resistance to cetuximab treatment. Further work is ongoing to characterize the molecular mechanisms underpinning let-7g mediated effect on anti-EGFR sensitivity in RAS wt CRC cells.
Citation Format: Jens C. Hahne, Andrea Lampis, Michele Ghidini, Margherita Ratti, Chiara Senti, Rodolfo Passalacqua, Luciano Cascione, Chiara Braconi, Owen Sansom, Matteo Fassan, Nicola Valeri. Expression of exosomal let-7g in biofluids and outcome in colon cancer patient treated with anti-EGFR therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2373.
Somatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in ...multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors.
Patients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety.
Sixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5–57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1–78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7–18.3 months); median OS was 16.8 months (95%CI 4.1–NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations.
Neratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population.
Trial registration number.NCT01953926 (ClinicalTrials.gov), 2013–002872-42 (EudraCT).
•Somatic HER2 mutations are a newly identified class of oncogenic drivers in several solid cancers.•HER2 mutations have an estimated incidence of 5% in cervical cancer and may be associated with a poor prognosis.•A subset of HER2 mutations are sensitive to inhibition by neratinib, an irreversible pan-HER tyrosine kinase inhibitor.•Neratinib monotherapy showed promising efficacy in heavily pretreated patients with HER2-mutant, cervical cancer.
Background
EMPOWER‐Lung 3, a randomized 2:1 phase 3 trial, showed clinically meaningful and statistically significant overall survival improvement with cemiplimab plus platinum‐doublet chemotherapy ...versus placebo plus chemotherapy for first‐line treatment of advanced non–small cell lung cancer. This study evaluated patient‐reported outcomes (PROs).
Methods
PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks) for the first six doses, and then at start of every three cycles, using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life‐Core 30 (QLQ‐C30) and Quality of Life‐Lung Cancer Module (QLQ‐LC13) questionnaires. Prespecified analyses included a longitudinal mixed‐effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis performed for global health status/quality of life (GHS/QoL) and all scales from the questionnaires. Between‐arm TTD comparisons were made using a stratified log‐rank test and proportional hazards model.
Results
A total of 312 patients were assigned to receive cemiplimab plus platinum‐doublet chemotherapy and 154 to receive placebo plus chemotherapy; 391 (83.9%) were male and the median age was 63.0 years (range, 25–84). For pain symptoms (EORTC QLQ‐C30), a statistically significant overall improvement from baseline (−4.98, 95% confidence interval CI −8.36 to −1.60, p = .004) and a statistically significant delay in TTD (hazard ratio, 0.39; 95% CI, 0.26–0.60, p < .0001) favoring cemiplimab plus chemotherapy were observed. Statistically significant delays in TTD, all favoring cemiplimab plus chemotherapy, were also observed in functioning and symptom scales. A significant overall improvement from baseline in GHS/QoL was seen for cemiplimab plus chemotherapy compared with nonsignificant overall change from baseline for placebo plus chemotherapy (1.69, 95% CI, 0.20–3.19 vs. 1.08, 95% CI, –1.34 to 3.51; between arms, p = .673). No analyses yielded statistically significant PRO results favoring placebo plus chemotherapy for any QLQ‐C30 or QLQ‐LC13 scale.
Conclusion
Cemiplimab plus chemotherapy resulted in significant overall improvement in pain symptoms and delayed TTD in cancer‐related and lung cancer–specific symptoms and functions.
Cemiplimab plus chemotherapy significantly improves pain in advanced lung cancer patients; significant delay in other symptom and function deterioration is also achieved. These results further support positive benefit‐risk profile of cemiplimab plus chemotherapy.
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Background: Vinflunine is the only chemotherapy agent for which there is a marketing authorisation in Europe for platinum-pretreated patients (pts) with mUC, based on a randomized ...phase III clinical trial. However, RW data regarding long-term efficacy and safety of vinflunine in unselected populations is needed. We conducted a systematic review gathering RW data from published observational European studies. Methods: Controlled studies and case series were excluded. We systematically explored the following endpoints: Overall Response Rate (ORR), Progression-Free Survival (PFS), Overall Survival (OS) and toxicity. Results: From 2014 to 2017, seven post-marketing studies including 750 pts were published: one was prospective and six were retrospective. Median ORR and median OS ranged from 13% to 29% and 6.3 to 11.9 months (mo) respectively (see Table below). In long-term survivors, OS reached 20.5 mo. Initial doses ranged from 250 to 320 mg/m2 adapted to patient’s conditions. In multivariate analysis, OS was found to be associated with the following risk-factors at baseline: ECOG PS >0, hemoglobin <10 g/dl, and presence of liver metastasis. The favorable safety profile demonstrated in randomized trials was confirmed. Main toxicity was hematological: neutropenia (G 3/4 in 1% to 23%) and anemia (G 3/4 in 4% to 33%). Constipation seemed to be less frequent than previously reported (G 3/4 in 5% to 22%). Conclusions: This is the largest experience of vinflunine use in platinum-pretreated pts with mUC. In our RW evidence, vinflunine shows both efficacy and a safe profile in an unselected patient population with similar criteria as in the pivotal trial. These findings reinforce the role of vinflunine in mUC, particularly if compared to evidence with taxanes or the increasing costs of immunotherapy.Table: see text
Abstract
Background: MicroRNAs (miRs) are small non-coding RNAs involved in cell homeostasis. miR dysregulation has been linked with activation of oncogenic pathways, cancer progression and clinical ...outcome in mCRC. Chemo-refractory mCRC patients are often treated with regorafenib, a multi-tyrosine kinase inhibitor with anti-angiogenic effect. Given the limited clinical benefits of regorafenib in unselected patient populations, there is an unmet need for better patient stratification and identification of mechanisms of resistance.
Methods: Serial liquid biopsies were obtained at baseline (BL) and monthly until disease progression (PD) in 43 patients treated with regorafenib for chemo-refractory mCRC in the context of a phase II clinical trial (PROSPECT-R). Tissue biopsies were obtained at BL, after 2 months and at PD within the same trial and used to establish Patient-Derived Organoids (PDOs) and for molecular analyses. PDOs co-cultures and PDO-xenotransplants were generated to study primary and acquired resistance to regorafenib. Liquid biopsies were also obtained from an additional cohort (n=97) of mCRC patients treated with regorafenib. MiR profiling was performed on baseline seras using NanoString nCounter platform and significant miRs were validated with digital droplet (dd)PCR in serum, plasma, PDOs and by In Situ Hybridization (ISH) in matching tissue biopsies. Functional experiments were performed in PDOs, PDO co-cultures and PDO-xenotransplants.
Results: MiR expression was tested in 43 BL in the PROSPECT-R trial. Up-regulation of miR-652-3p was associated with poor PFS and OS. These results were validated by ddPCR on the same serum samples, matching plasmas and organoids. ISH confirmed upregulation of this miR in sequential tissues biopsies, PDOs and PDO-xenotransplants of patients with primary and acquired resistance to regorafenib. The same findings were confirmed in the validation cohort.
Functional experiments showed that miR-652-3p upregulation has significant effects on cancer cell migration. Up and down-regulation of miR-652-3p upon regorafenib treatment translated in a significant effect on cell viability in PDO co-cultures and liver PDO-xenotransplants. RNA-sequencing analysis of miR-652-3p over-expressing organoids showed downregulation of several components of the serine synthesis pathway. Among them, phosphoserine aminotransferase (PSAT1) was validated as a miR-652-3p direct target. Rescue experiments confirmed that PSAT1 over-expression and silencing lead to increase sensitivity and resistance to regorafenib respectively via cell and non-cell autonomous regulation of autophagy.
Conclusions: Our data suggest that miR-652-3p may be uses as a prognostic/predictive biomarker for the selection of treatment and provide mechanics insight on regorafenib resistance.
Citation Format: Somaieh Hedayat, Andrea Lampis, George Vlachogiannis, khurum Khan, Silvia Marchetti, Matteo Fassan, Michele Ghidini, Ruwaida Begum, Marta Schirripa, Rodolfo Passalacqua, David Cunningham, Fotios Loupakis, Nicola Valeri. MicroRNA deregulation of the serine synthesis pathway controls intrinsic and non-cell autonomous mechanism of resistance to Regorafenib in metastatic colorectal cancer (mCRC) abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5720.
Summary
Gastric cancer (GC) is one of the most common malignancies and a major cause of cancer-related deaths worldwide. Its incidence has significantly declined over the last few decades, probably ...due to the identification of specific etiologic agents such as Helicobacter pylori and other dietary and environmental risk factors. Nevertheless, most of the cases are unfortunately diagnosed at an advanced stage justifying median overall survival rates frequently not exceeding one year. Palliative combination chemotherapy usually represented by a platinum-based doublet is the mainstay of treatment in the metastatic setting. Adding a third drug such as an anthracycline or a taxane has been shown to improve response rate and provide limited survival benefits in fit selected patients. Unlike other tumors, the introduction of molecularly targeted drugs in the medical armamentarium for GC is relatively recent with trastuzumab and ultimately ramucirumab constituting the only agents approved to date. Recent advances in the understanding of GC biology have led to the development of novel targeted therapies holding the promise to further improve treatment outcomes. The aim of this paper is to review the main available data coming from clinical trials of targeted drugs and to describe some of the most interesting molecules in clinical development in GC. These include drugs targeting EGFR, angiogenesis, c-MET, FGFR2, mTOR and immune checkpoints.
Abstract Oligometastatic non-small cell lung cancer (NSCLC), defined as a disease with low metastatic burden and limited organ involvement, is conceived as an intermediate condition between a truly ...localised disease and a widely metastatic tumour. Traditionally, local ablative therapies (LATs), such as surgery and radiotherapy, have been limited to symptoms' palliation in advanced NSCLC. Several retrospective studies suggest that using local ablative therapy for oligometastatic disease could offer good local control of the disease and improvement in terms of progression-free survival. The first randomised study of local consolidative therapy versus maintenance therapy or observation in oligometastatic NSCLC has been recently published. The results of this phase II trial showed an impressive improvement in median progression-free survival with local therapy and a delay in the appearance of new lesions, suggesting a systemically extended benefit of consolidation therapies. Nevertheless, further confirmation of this evidence with additional future trials is needed to definitively consider the combination of local treatment techniques with novel systemic agents recently approved for NSCLC therapy, such as immune checkpoint inhibitors.
The multi-kinase inhibitor (mKi) regorafenib has demonstrated efficacy in chemorefractory patients with metastatic colorectal cancer (mCRC). However, lack of predictive biomarkers and concerns over ...significant toxicities hamper the use of regorafenib in clinical practice.
Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemorefractory patients with mCRC treated with regorafenib in a phase II clinical trial (PROSPECT-R n = 40; NCT03010722) and in a multicentric validation cohort (n = 241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish patient-derived organoids (PDO) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital-droplet PCR and/or ISH in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses.
Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652-3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a "control" group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modeled regorafenib response observed in vivo and in patients, and showed that MIR652-3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option.
Our results identify MIR652-3p as a potential biomarker and as a driver of cell and non-cell-autonomous mechanisms of resistance to regorafenib.
There is currently no standard therapy to reduce the recurrence rate after surgery for renal cell carcinoma (RCC). The aim of this study was to assess efficacy and safety of adjuvant treatment with ...low doses of interleukin-2 (IL-2)+interferon-α (IFN-α) in operable RCC. The patients were randomized 1:1 to receive a 4-week cycle of low-dose IL-2+IFN-α or observation after primary surgery for RCC. Treatment cycles were repeated every 4 months for the first 2 years and every 6 months for the subsequent 3 years. The primary endpoint was recurrence-free survival (RFS); safety; and overall survival (OS) were secondary endpoints. ClinicalTrials.gov registration number was NCT00502034. 303/310 randomized patients (156 in the immunotherapy arm and 154 in the observation group) were evaluable at the intention-to-treat analyses. The 2 arms were well balanced. At a median follow-up of 52 months (range, 12-151 mo), RFS, and OS were similar, with an estimated hazard ratio (HR) of 0.84 95% confidence interval (CI), 0.54-1.31; P=0.44 and of 1.07 (95% CI, 0.64-1.79; P=0.79), respectively in the 2 groups. Unplanned, subgroup analysis showed a positive effect of the treatment for patients with age 60 years and younger, pN0, tumor grades 1-2, and pT3a stage. Among patients with the combined presence of ≥ 2 of these factors, immunotherapy had a positive effect on RFS (HR=0.44; 95% CI, 0.24-0.82; P ≤ 0.01), whereas patients with <2 factors in the treatment arm exhibited a significant poorer OS (HR=2.27; 95% CI, 1.03-5.03 P=0.037). Toxicity of immunotherapy was mild and limited to World Health Organization grade 1-2 in most cases. Adjuvant immunotherapy with IL-2+IFN-α showed no RFS or OS improvement in RCC patients who underwent radical surgery. The results of subset analysis here presented are only hypothesis generating.
Introduction: Neoadjuvant chemoradiotherapy (CTRT) is the current standard of care for treatment of locally advanced cancer of the esophagus or gastroesophageal junction. Many efforts have been made ...over the last years to identify the best chemotherapy and radiotherapy combination regimen, but specific randomized trials addressing this issue are still lacking.
Areas covered: A systematic review of the literature was performed searching in PubMed all published studies of combinations CTRT regimens for operable or unresectable esophageal cancer to describe activity and toxicity. Studies considered were prospective series or clinical phase II-III trials including at least 40 patients and published in English language.
Expert commentary: Long-term results of CROSS trial have established RT combined with carboplatin plus paclitaxel chemotherapy as the preferred neoadjuvant treatment option for both squamous and adenocarcinoma of the esophagus. More effective multimodal treatment strategies integrating novel biological agents including immunotherapy and based on an extensive molecular tumor characterization are eagerly awaited.
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