Biomarker and pharmacodynamic activity of the transforming growth factor-beta (TGFß) inhibitor SAR439459 as monotherapy and in combination with cemiplimab in a phase I clinical study in patients with advanced solid tumors.

SAR439459, a 'second-generation' human anti-transforming growth factor-beta (TGFß) monoclonal antibody, inhibits all TGFß isoforms and improves the antitumor activity of anti-programmed cell death protein-1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first-in-human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose-escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose-expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFß, downregulation of TGFß-pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from 'immune-excluded' to 'immune-infiltrated' phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFß1 was more consistently elevated followed by TGFß2, whereas TGFß3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFß alteration. However, further studies are needed to identify biomarkers of response.

The host Rab9a/Rab32 axis is actively recruited to the Trypanosoma cruzi parasitophorous vacuole and benefits the infection cycle.

Trypanosoma cruzi, the etiological agent of Chagas disease is a protozoan parasite that infects phagocytic and non-phagocytic mammalian cells. At early stages of infection, trypomastigotes, the infective forms of this parasite, localize in a vesicular compartment called the T. cruzi parasitophorous vacuole until the exit of parasites to the host cell cytoplasm where continue their infective cycle. Rab proteins participate in the membrane traffic's molecular machinery, functioning as central regulators of vesicle recognition and transport. In previous work, we demonstrated that endocytic Rabs are key factors of the T. cruzi infection process in non-phagocytic cells, regulating the formation and the maturation of the vacuole. In this work, we identified and characterized other molecular components of the vesicular transport pathways and their participation in the T. cruzi infection. We found that Rab9a and Rab32, two regulators of the endocytic and autophagic pathways, were actively recruited to the T. cruzi vacuoles and favored the late stages of the infective process. The recruitment was specific and dependent on T. cruzi protein synthesis. Interestingly, Rab32 association depends on the presence of Rab9a in the vacuolar membrane, while the inhibition of the cysteine-protease cruzipain, a T. cruzi virulence factor, significantly decreases both Rab9a and Rab32 association with the vacuole. In summary, this work showed for the first time that specific molecules produced and secreted by the parasite can subvert intracellular components of host cells to benefit the infection. These new data shed light on the complex map of interactions between T. cruzi and the host cell and introduce concepts that can be useful in finding new forms of intervention against this parasite in the future.

Autophagy as an innate immunity response against pathogens: a Tango dance.

Intracellular infections as well as changes in the cell nutritional environment are main events that trigger cellular stress responses. One crucial cell response to stress conditions is autophagy. During the last 30 years, several scenarios involving autophagy induction or inhibition over the course of an intracellular invasion by pathogens have been uncovered. In this review, we will present how this knowledge was gained by studying different microorganisms. We intend to discuss how the cell, via autophagy, tries to repel these attacks with the objective of destroying the intruder, but also how some pathogens have developed strategies to subvert this. These two fates can be compared with a Tango, a dance originated in Buenos Aires, Argentina, in which the partner dancers are in close connection. One of them is the leader, embracing and involving the partner, but the follower may respond escaping from the leader. This joint dance is indeed highly synchronized and controlled, perfectly reflecting the interaction between autophagy and microorganism.

Autophagy in protists and their hosts: When, how and why?

Pathogenic protists are a group of organisms responsible for causing a variety of human diseases including malaria, sleeping sickness, Chagas disease, leishmaniasis, and toxoplasmosis, among others. These diseases, which affect more than one billion people globally, mainly the poorest populations, are characterized by severe chronic stages and the lack of effective antiparasitic treatment. Parasitic protists display complex life-cycles and go through different cellular transformations in order to adapt to the different hosts they live in. Autophagy, a highly conserved cellular degradation process, has emerged as a key mechanism required for these differentiation processes, as well as other functions that are crucial to parasite fitness. In contrast to yeasts and mammals, protist autophagy is characterized by a modest number of conserved autophagy-related proteins (ATGs) that, even though, can drive the autophagosome formation and degradation. In addition, during their intracellular cycle, the interaction of these pathogens with the host autophagy system plays a crucial role resulting in a beneficial or harmful effect that is important for the outcome of the infection. In this review, we summarize the current state of knowledge on autophagy and other related mechanisms in pathogenic protists and their hosts. We sought to emphasize when, how, and why this process takes place, and the effects it may have on the parasitic cycle. A better understanding of the significance of autophagy for the protist life-cycle will potentially be helpful to design novel anti-parasitic strategies.

Liquid Biopsies for Circulating Tumor DNA Detection May Reveal Occult Hematologic Malignancies in Patients With Solid Tumors.

PURPOSE: High-risk clonal hematopoiesis (CH) is frequently incidentally found in patients with solid tumors undergoing plasma cell-free DNA sequencing. Here, we aimed to determine if the incidental detection of high-risk CH by liquid biopsy may reveal occult hematologic malignancies in patients with solid tumors. MATERIALS AND METHODS: Adult patients with advanced solid cancers enrolled in the Gustave Roussy Cancer Profiling study (ClinicalTrials.gov identifier: NCT04932525) underwent at least one liquid biopsy (FoundationOne Liquid CDx). Molecular reports were discussed within the Gustave Roussy Molecular Tumor Board (MTB). Potential CH alterations were observed, and patients referred to hematology consultation in the case of pathogenic mutations in JAK2, MPL, or MYD88, irrespective of the variant allele frequency (VAF), or in DNMT3A, TET2, ASXL1, IDH1, IDH2, SF3B1, or U2AF1 with VAF ≥ 10%, while also considering patient cancer-related prognosis. TP53 mutations were discussed case-by-case. RESULTS: Between March and October 2021, 1,416 patients were included. One hundred ten patients (7.7%) carried at least one high-risk CH mutation: DNMT3A (n = 32), JAK2 (n = 28), TET2 (n = 19), ASXL1 (n = 18), SF3B1 (n = 5), IDH1 (n = 4), IDH2 (n = 3), MPL (n = 3), and U2AF1 (n = 2). The MTB advised for hematologic consultation in 45 patients. Overall, 9 patients of 18 actually addressed had confirmed hematologic malignancies that were occult in six patients: two patients had myelodysplastic syndrome, two essential thrombocythemia, one a marginal lymphoma, and one a Waldenström macroglobulinemia. The other three patients were already followed up in hematology. CONCLUSION: The incidental findings of high-risk CH through liquid biopsy may trigger diagnostic hematologic tests and reveal an occult hematologic malignancy. Patients should have a multidisciplinary case-by-case evaluation.

Sequence analyses of relapsed or refractory diffuse large B-cell lymphomas unravel three genetic subgroups of patients and the GNA13 mutant as poor prognostic biomarker, results of LNH-EP1 study.

Advances in molecular profiling of newly diagnosed diffuse large B-cell lymphoma (DLBCL) have recently refine genetic subgroups. Genetic subgroups remain undetermined at the time of relapse or refractory (RR) disease. This study aims to decipher genetic subgroups and search for prognostic molecular biomarkers in patients with RR-DLBCL. From 2015 to 2021, targeted next-generation sequencing analyses of germline-matched tumor samples and fresh tissue from RR-DLBCL patients were performed. Unsupervised clustering of somatic mutations was performed and correlations with patient outcome were sought. A number of 120 patients with RR-DLBCL were included in LNH-EP1 study and a molecular tumor landscape was successfully analyzed in 87% of patients (104/120 tumor samples). The median age was 67.5 years (range 27.4-87.4), median number of previous treatments was 2 (range 1-9). The most frequently mutated genes were TP53 (n = 53 mutations; 42% of samples), CREBBP (n = 39; 32%), BCL2 (n = 86; 31%), KMT2D (n = 39; 28%) and PIM1 (n = 54; 22%). Unsupervised clustering separated three genetic subgroups entitled BST (enriched in BCL2, SOCS1, and TNFRSF14 mutations); TKS (enriched in TP53, KMT2D, and STAT6 mutations); and PCM (enriched in PIM1, CD79B, and MYD88 mutations). Median overall survival (OS) was 11.0 (95% confidence interval [CI]: 8.1-12.6) months. OS was not significantly different between the three genetic subgroups. GNA13 mutant was significantly associated with an increased risk of death (hazard ratio: 6.6 [95% CI: 2.1-20.6]; p = .0011) and shorter OS (p = .0340). At the time of relapse or refractory disease, three genetic subgroups of DLBCL patients were delineated, which could help advance precision molecular medicine programs.

Implementing the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets in a Comprehensive Profiling Program: Impact on Precision Medicine Oncology.

PURPOSE: To facilitate implementation of precision medicine in clinical management of cancer, the European Society of Medical Oncology proposed in 2018 a new scale to harmonize and standardize the reporting and interpretation of clinically relevant genomics data (ESMO Scale of Actionability of molecular Targets [ESCAT]). This study aims to characterize the clinical impact of matching targetable genomic alterations (GAs) in patients with advanced cancer according to ESCAT. MATERIAL AND METHODS: Analysis of next-generation sequencing results from 552 patients is included in two prospective precision medicine studies at Gustave Roussy. End points included objective response rates, progression-free survival, and overall survival according to ESCAT. RESULTS: Molecular data from 516 patients were available and discussed within a Molecular Tumor Board. The most common tumor types were GI (n = 164; 30%), lung (n = 137; 25%), and urologic tumors (n = 68; 13%). Overall, 379 GAs were considered as actionable targets according to ESCAT in 348 (67%) patients. In 31 (6%) patients, two concomitant actionable targets were identified. On the basis of ESCAT, GAs were considered to be classified as tier I in 120 patients (29%), II in 25 patients (5%), III in 80 patients (16%), and IV in 153 patients (30%). A total of 136 patients (27%) received a matched therapy. ESCAT was significantly associated with objective response rates and clinical benefit rates. The median progression-free survival was 6.5 months (95% CI, 4.2 to 8.9), 3 months (95% CI, 1 to not available), 3 months (95% CI, 2.2 to 3.8), and 4 months (95% CI, 2.8 to 6.3) for ESCAT I, II, III, and IV, respectively (P = .0125). CONCLUSION: Implementation of ESCAT classification for clinical decision making by Molecular Tumor Board is feasible and useful to better tailor therapies in patients with cancer.

Predicting Immunotherapy Outcomes in Older Patients with Solid Tumors Using the LIPI Score.

Immunotherapy with immune checkpoint blockers (ICB) represents a valid therapeutic option in older patients for several solid cancer types. However, most of the data concerning efficacy and adverse events of ICB available are derived from younger and fitter patients. Reliable biomarkers are needed to better select the population that will benefit from ICB especially in older patients who may be at a higher risk of developing immune-related adverse events (irAEs) with a greater impact on their quality of life. The Lung Immune Prognostic Index (LIPI) is a score that combines pretreatment dNLR (neutrophils/[leukocytes − neutrophils]) and lactate dehydrogenase (LDH) and is correlated with outcomes in patients treated with ICB in non-small-cell lung cancer. We aimed to assess the impact of LIPI in ICB outcomes in a dedicated cohort of older patients. The primary objective was to study the prognostic role of LIPI score in patients aged 70 years or above in a real-life population treated with anti-programmed death-(ligand)1 (anti PD-(L)1). dNLR and LDH were collected in a prospective cohort of patients aged 70 years or above treated with PD-(L)1 inhibitors with metastatic disease between June 2014 and October 2017 at Gustave Roussy. LIPI categorizes the population into three different prognostic groups: good (dNLR ≤ 3 and LDH ≤ ULN­upper normal limit), intermediate (dNLR > 3 or LDH > ULN), and poor (dNLR > 3 and LDH > ULN). Anti PD-(L)1 benefit was analyzed according to overall survival (OS), progression free survival (PFS), and overall response rate (ORR) using RECIST v1.1. criteria. In the 191 older patients treated, most of them (95%) were ICB-naïve, and 160 (84%) had an ECOG performance status of 0−1 with a median age at ICB treatment of 77 (range, 70−93). The most common tumor types were melanoma (66%) and non-small-cell lung cancer (15%). The median follow-up duration was 18.8 months (95% CI 14.7−24.2). LIPI classified the population into three different groups: 38 (23%) patients had a good LIPI score, 84 (51%) had an intermediate LIPI score, and 43 (26%) had a poor LIPI score. The median OS was 20.7 months [95% CI, 12.6−not reached] compared to 11.2 months [95% CI, 8.41−22.2] and 4.7 months [95% CI, 2.2−11.3] in patients with a good, intermediate, and poor LIPI score, respectively (p = 0.0003). The median PFS was 9.2 months [95% CI, 6.2−18.1] in the good LIPI group, 7.2 months [95% CI, 5.4−13] in the intermediate LIPI group, and 3.9 months [95% CI, 2.3−8.2] in the poor LIPI group (p = 0.09). The rate of early death (OS < 3 months) was 37% in the poor LIPI group compared to 5% in the good LIPI group (<0.001). Poor LIPI score was associated with a poorer outcome in older patients treated with anti PD-(L)1. LIPI is a simple and accessible worldwide tool that can serve as a prognostic factor and can be useful for stratification benefit from ICB.

Induction of Autophagy by Ursolic Acid Promotes the Elimination of Trypanosoma cruzi Amastigotes From Macrophages and Cardiac Cells.

Chagas disease, caused by the parasite Trypanosoma cruzi, is an infectious illness endemic to Latin America and still lacks an effective treatment for the chronic stage. In a previous study in our laboratory, we established the protective role of host autophagy in vivo during T. cruzi infection in mice and proposed this process as one of the mechanisms involved in the innate immune response against this parasite. In the search for an autophagy inducer that increases the anti-T. cruzi response in the host, we found ursolic acid (UA), a natural pentacyclic triterpene with many biological actions including autophagy induction. The aim of this work was to study the effect of UA on T. cruzi infection in vitro in the late infection stage, when the nests of intracellular parasites are forming, in both macrophages and cardiac cells. To test this effect, the cells were infected with T. cruzi for 24 h and then treated with UA (5-10 µM). The data showed that UA significantly decreased the number of amastigotes found in infected cells in comparison with non-treated cells. UA also induced the autophagy response in both macrophages and cardiac cells under the studied conditions, and the inhibition of this pathway during UA treatment restored the level of infection. Interestingly, LC3 protein, the main marker of autophagy, was recruited around amastigotes and the acidic probe LysoTracker localized with them, two key features of xenophagy. A direct cytotoxic effect of UA was also found on trypomastigotes of T. cruzi, whereas epimastigotes and amastigotes displayed more resistance to this drug at the studied concentrations. Taken together, these data showed that this natural compound reduces T. cruzi infection in the later stages by promoting parasite damage through the induction of autophagy. This action, in addition to the effect of this compound on trypomastigotes, points to UA as an interesting lead for Chagas disease treatment in the future.

Biological features of TcM: A new Trypanosoma cruzi isolate from Argentina classified into TcV lineage.

Trypanosoma cruzi, the etiologic agent of Chagas disease (CD) presents a wide genetic and phenotypic diversity that is classified into seven lineages or discrete typing units (DTU: TcI to TcVI and Tcbat). Although isolates and strains that belong to a particular group can share some attributes, such as geographic distribution, others like growth rate, cell tropism, and response to treatment can be highly variable. In addition, studies that test new trypanocidal drugs are frequently conducted on T. cruzi strains maintained for a long time in axenic culture, resulting in changes in parasite virulence and other important features. This work aimed to isolate and characterize a new T. cruzi strain from a chronic Chagas disease patient. The behavior of this isolate was studied by using standard in vitro assays and in vivo mice infection tests and compared with the T. cruzi Y strain (TcY), broadly used in research laboratories worldwide. Data showed that TcM behaves as a slow-growing strain in vitro that develops chronic infections in mice and displays high tropism to muscular tissues, in accordance with its clinical performance. In contrast, the Y strain behaved as an acute strain that can infect different types of cells and tissues. Interestingly, TcM, which belongs to DTU TcV, is more susceptible to benznidazole than TcY, a TcII strain considered moderately resistant to this drug. These differential properties contribute to the characterization of a TcV strain, one of the main lineages in the southern countries of South America, and open the possibility to introduce changes that improve the management of Chagas patients in the future.

PALLIA 10 score in phase I cancer studies.

OBJECTIVE: Phase I clinical trials usually include patients with advanced disease who have failed standard therapies and should benefit from early palliative care. We try to assess whether PALLIA 10, a score developed in France to help identify patients who might benefit from a palliative care referral, could be used in a phase I department trial. METHODS: We assessed PALLIA 10 score and other prognostic factors in patients enrolled in phase I trials at Gustave Roussy Cancer Center prospectively during two periods of time (cohort 1 (C1) and 2 (C2)). A double-blind assessment of the PALLIA 10 score was done in C2 by a palliative care specialist and a nurse. RESULTS: From 1 July 2018 to 1 November 2018 (C1) and from 1 December 2020 to 16 April 2021 (C2), 86 patients were assessed in C1 and 302 in C2. Median PALLIA 10 was very low in both cohorts (median 1, range 1-5 in C1 and 1-8 in C2). On C1 and C2, 12% and 5% of patients had a dedicated palliative consultation. In C2, assessment of PALLIA 10 score was significantly different between palliative care physician (median 5, range 3-8), phase I physician (median 1, range 1-6) and phase I nurse (median 3, range 1-8) (p<0.001). CONCLUSION: Median PALLIA 10 score was low when assessed by the phase I physician, which suggests the need for a better tool and appropriate clinician's education to implement early palliative care in clinical practice and trials.

Epigenetic gene alterations in metastatic solid tumours: results from the prospective precision medicine MOSCATO and MATCH-R trials.

INTRODUCTION: Although the role of epigenetic alterations in oncogenesis has been well studied, their prevalence in metastatic solid tumours is still poorly described. We therefore aimed at: (i) describing the presence of epigenetic gene alterations (EGA) - defined by an alteration in a gene encoding an epigenetic regulator; and (ii) evaluating their relationship with clinical characteristics and outcome in patients (pts) included in prospective molecular profiling trials. MATERIALS AND METHODS: On-purpose tumour biopsies from pts with metastatic solid tumours enrolled in the Gustave Roussy-sponsored MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials were molecularly profiled using whole exome sequencing (WES). Alterations in 176 epigenetic genes were assessed and classified as pathogenic variants (PV) or non-pathogenic variants by a molecular tumour board. Clinical characteristics and outcome were collected. RESULTS: Between Dec 2011 and Oct 2016, WES was successfully performed in 292 pts presenting various solid tumours. We found 496 epigenetic gene alterations in 134 patients (49%), including 237 pathogenic variants in 86 patients; 63 tumour samples (47%) presented ≥3 EGAs. The median number of previous treatment lines was 3 (1-10). The most frequently altered genes were KMT2D and KMT2C (16% each), ARID1A and SETD2 (10% each) and KMT2A (8%).; 31% of EGA co-occurred with a driver gene alteration (p &lt; 0.001). Outcome was not correlated with the presence of EGA. CONCLUSIONS: Epigenetic alterations occur frequently in metastatic solid tumours. With the current development of epigenetic modifiers, they increasingly represent actionable targets. Such genes should now be systematically analysed in molecular profiling studies.

Safety, recommended dose, efficacy and immune correlates for nintedanib in combination with pembrolizumab in patients with advanced cancers.

BACKGROUND: We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). METHODS: In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. RESULTS: A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1-2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55-40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4+ PD1+ OX40+ T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP+ dendritic cells, CD3+ T cells and FOXP3+ Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4+ CXCR3+ CXCR5- memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels. CONCLUSION: Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02856425 . Registered August 4, 2016 - Prospectively registered.

Next-Generation Sequencing on Circulating Tumor DNA in Advanced Solid Cancer: Swiss Army Knife for the Molecular Tumor Board? A Review of the Literature Focused on FDA Approved Test.

FDA-approved next-generation sequencing assays based on cell-free DNA offers new opportunities in a molecular-tumor-board context thanks to the noninvasiveness of liquid biopsy, the diversity of analyzed parameters and the short turnaround time. It gives the opportunity to study the heterogeneity of the tumor, to elucidate complex resistance mechanisms and to adapt treatment strategies. However, lowering the limit of detection and increasing the panels' size raise new questions in terms of detection of incidental germline alterations, occult malignancies and clonal hematopoiesis of indeterminate potential mutations. In this review, after a technological discussion and description of the common problematics encountered, we establish recommendations in properly using these FDA-approved tests in a molecular-tumor-board context.

Clinical activity of CC-90011, an oral, potent, and reversible LSD1 inhibitor, in advanced malignancies.

BACKGROUND: CC-90011 is an oral, potent, selective, reversible inhibitor of lysine-specific demethylase 1 (LSD1) that was well tolerated, with encouraging activity in patients who had advanced solid tumors or relapsed/refractory marginal zone lymphoma. The authors present long-term safety and efficacy and novel pharmacodynamic and pharmacokinetic data from the first-in-human study of CC-90011. METHODS: CC-90011-ST-001 (ClincalTrials.gov identifier NCT02875223; Eudract number 2015-005243-13) is a phase 1, multicenter study in which patients received CC-90011 once per week in 28-day cycles. The objectives were to determine the safety, maximum tolerated dose, and/or recommended phase 2 dose (primary) and to evaluate preliminary efficacy and pharmacokinetics (secondary). RESULTS: Sixty-nine patients were enrolled, including 50 in the dose-escalation arm and 19 in the dose-expansion arm. Thrombocytopenia was the most common treatment-related adverse event and was successfully managed with dose modifications. Clinical activity with prolonged, durable responses were observed, particularly in patients who had neuroendocrine neoplasms. In the dose-escalation arm, one patient with relapsed/refractory marginal zone lymphoma achieved a complete response (ongoing in cycle 58). In the dose-expansion arm, three patients with neuroendocrine neoplasms had stable disease after nine or more cycles, including one patient who was in cycle 46 of ongoing treatment. CC-90011 decreased levels of secreted neuroendocrine peptides chromogranin A, progastrin-releasing peptide, and RNA expression of the blood pharmacodynamic marker monocyte-to-macrophage differentiation-associated. CONCLUSIONS: The safety profile of CC-90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once-per-week dosing support further exploration of CC-90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies.

Radiological patterns of tumour progression in patients treated with a combination of immune checkpoint blockers and antiangiogenic drugs.

BACKGROUND: Immune checkpoint blockers (ICBs) in combination with antiangiogenic drugs showed synergistic efficacy in several tumour types. New patterns of progression have recently been defined upon treatment with ICB alone including atypical responses such as pseudoprogression (PsPD), dissociated response and hyperprogressive disease (HPD). This study aimed to describe the patterns of response observed in patients treated with combination ICB with antiangiogenic drugs. METHODS: We conducted a monocentric retrospective analysis of patients (pts) enrolled in phase I trials at Gustave Roussy assessing the combination of ICB and antiangiogenic drugs. Radiological CT scans were centrally reviewed by a senior radiologist according to iRECIST criteria including progressive disease (PD), partial response (PR) and stable disease (SD). HPD was defined as a progression at the first evaluation with a delta tumour growth rate exceeding 50%. PsPD was defined as initial progression followed by stabilisation or decrease of tumour size, DisR as a concomitant size decrease in some tumour lesions and size increase in others. Both PsPD and DisR are defined as atypical responses. Overall response rate included PR and complete response (CR) and disease control rate included PR, CR and SD. RESULTS: Between December 2016 and June 2020, 111 pts were included. The median follow up was 12.8 months (11.3-15.1). The most common tumour types were lung and pleura (20%), kidney (18%) and bladder (17%). The overall response rate and disease control rate were 21.6% (n = 24) and 59% (n = 65), respectively. Twenty-one patients (19%) experienced PD as the best response. PsPD, DisR and HPD were observed in 4 (3.6%), 11 (9.9%) and 7 (6.3%) pts, respectively. DisR and PsPD were associated with longer iProgression Free Survival (median: 6.9 and 18.9 months, respectively) and iOverall Survival (median: 28.4 and 31.1 months, respectively) than a median of SD in immune progression-free survival (median: 4.2 months) and immune overall survival (median: 12.7 months). CONCLUSION: Patients treated with ICBs and antiangiogenic agents display atypical responses. Survival might be longer in patients with DisR responses and PsPD disease than patients with HPD, PD and SD.

Phase I Study of JNJ-74699157 in Patients with Advanced Solid Tumors Harboring the KRAS G12C Mutation.

BACKGROUND: Patients with KRAS-mutant cancers have limited treatment options. Here we present a phase I study of JNJ-74699157, an oral, selective, covalent inhibitor of the KRAS G12C isoform, in patients with advanced cancer harboring the KRAS G12C mutation. METHODS: Eligible patients (aged ≥18 years) who had previously received or were ineligible for standard treatment received JNJ-74699157 once daily on a 21-day cycle. Dose escalation was guided by a modified continual reassessment method. RESULTS: Ten patients (100 mg: 9 and 200 mg: 1) were enrolled. Tumor types included non-small cell lung cancer (n = 5), colorectal cancer (n = 4), and carcinoma of unknown primary site (n = 1). The median age was 65 (range: 36-74) years and median treatment duration was 2.91 (range: 0.5-7.5) months. Dose-limiting toxicities of grades 3-4 increased blood creatinine phosphokinase (CPK) were observed in 100 mg and 200 mg dose levels. The most common adverse event was increased blood CPK (6 patients). No significant clinical benefit was observed; the best response was stable disease in 4 patients (40%). CONCLUSION: Based on dose-limiting skeletal muscle toxicities and the lack of efficacy at the 100 mg dose, further enrollment was stopped. The safety profile of JNJ-74699157 was not considered favorable for further clinical development. CLINICALTRIALS.GOV IDENTIFIER: NCT04006301.

The Molecular Tumor Board Portal supports clinical decisions and automated reporting for precision oncology.

There is a growing need for systems that efficiently support the work of medical teams at the precision-oncology point of care. Here, we present the implementation of the Molecular Tumor Board Portal (MTBP), an academic clinical decision support system developed under the umbrella of Cancer Core Europe that creates a unified legal, scientific and technological platform to share and harness next-generation sequencing data. Automating the interpretation and reporting of sequencing results decrease the need for time-consuming manual procedures that are prone to errors. The adoption of an expert-agreed process to systematically link tumor molecular profiles with clinical actions promotes consistent decision-making and structured data capture across the connected centers. The use of information-rich patient reports with interactive content facilitates collaborative discussion of complex cases during virtual molecular tumor board meetings. Overall, streamlined digital systems like the MTBP are crucial to better address the challenges brought by precision oncology and accelerate the use of emerging biomarkers.

Case Report: Response to Immunotherapy, Can Radiotherapy Be a Troublemaker?

Immunotherapy has dramatically changed the treatment landscape for several tumor types. However, the impact of previous radiotherapy (RT) on response to immunotherapy is still unknown. We report the case of a 58-year-old female diagnosed with a squamous anal cell carcinoma previously treated with RT and having a dissociated response to anti-PD1 agent. An extensive analysis of the immune contexture performed on the tissue collected from both previously RT-treated and RT-untreated lesions confirmed differences on immune microenvironment, highlighting the potential impact of radiotherapy on the immune response.