Publications by authors named "Antoine Italiano"

256 Publications

High Prevalence of 5T4/Trophoblast Glycoprotein in Soft Tissue Sarcomas.

Cancers (Basel) 2021 Sep 28;13(19). Epub 2021 Sep 28.

Byondis B.V., Microweg 22, 6503 GB Nijmegen, The Netherlands.

The expression of 5T4/trophoblast glycoprotein was evaluated in several histological subtypes of soft tissue sarcoma (STS) to determine whether the prevalence and level of expression of this membrane-associated glycoprotein is sufficient for use in targeted therapies. Tumor tissue microarrays containing cores from different histological subtypes of STS were stained using a standardized immunohistochemical staining method to detect 5T4; the level of staining was assessed using a semi-quantitative scoring method. No 5T4 staining was seen in the angiosarcomas and liposarcomas investigated in this study. 5T4 staining in the other STS subtypes was seen in more than 50% of cases, warranting further investigation into whether this antigen could evoke an anti-tumor immune response or can be used as target for the delivery of more potent toxins through antibody drug conjugates.
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http://dx.doi.org/10.3390/cancers13194841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508483PMC
September 2021

Adjuvant imatinib in GIST patients harboring exon 9 KIT mutations: results from a multi-institutional European retrospective study.

Clin Cancer Res 2021 Oct 6. Epub 2021 Oct 6.

Medical Oncology Department, Hogar.

Purpose: The effect of high-dose imatinib (800 mg/d) on survival in the adjuvant treatment of patients with resected KIT exon-9 mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopathological variables with survival was evaluated in a large multi-institutional European cohort.

Methods: Data from 185 patients were retrospectively collected in 23 European GIST reference centers. Propensity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Univariate and multivariate unweighted and weighted Cox proportional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival.

Results: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated to the survival outcomes (RFS: HR 1.24, 95% CI 0.79-1.94; mRFS: HR 1.69, 95% CI 0.92-3.10; IFFS: HR 1.35, 95% CI 0.79-2.28). The variables consistently associated with worse survival outcomes were high mitotic index and non-gastric tumor location.

Conclusion: In this retrospective series of KIT exon 9-mutated GIST patients treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1665DOI Listing
October 2021

Impact of Disease Evolution on Efficacy Outcomes From Larotrectinib in Patients With Locally Advanced or Metastatic Tropomyosin Receptor Kinase Fusion-Positive Solid Tumors.

JCO Precis Oncol 2021 13;5. Epub 2021 Sep 13.

Bayer Pharmaceuticals, Basel, Switzerland.

Neurotrophic tyrosine receptor kinase () gene fusions encode oncogenic, chimeric tropomyosin receptor kinase (TRK) proteins. Larotrectinib, an approved TRK inhibitor, is efficacious in locally advanced or metastatic (adv/met) TRK fusion cancer. We evaluated the time from initial diagnosis to locally advanced or metastatic disease and to initiation of larotrectinib treatment as well as larotrectinib impact on disease course.

Materials And Methods: Patients were grouped by prior lines of therapy (0, 1-2, and ≥ 3) and pre-larotrectinib duration of adv/met disease (short [< 3.5 months], medium [3.5 to < 15.7 months], and long [≥ 15.7 months]). Overall response rate (ORR), duration of response (DOR), and progression-free survival were assessed.

Results: One hundred sixty-four patients were evaluated. The median time from initial diagnosis to development of locally adv/met stage was 2.1 months; the duration of pre-larotrectinib adv/met disease was 7.3 months (n = 153). In patients with 0, 1-2, and ≥ 3 prior lines of therapy, the median time from diagnosis to adv/met stage was 0.9, 1.2, and 9.4 months, and 1.5, 5.8, and 29.0 months from adv/met disease to larotrectinib initiation, respectively. Clinical outcomes were independent of line of therapy (ORR: 86%, 63%, and 80%, respectively; median DOR: 27.6, not reached, and 32.9 months), and similar across subgroups of short, medium, and long duration of pre-larotrectinib adv/met disease status (ORR: 88%, 65%, and 69%, respectively; median DOR: not reached, 27.6, and 32.9 months).

Conclusion: The short time from initial diagnosis to adv/met stage before larotrectinib suggests that gene fusion does not generally have a positive prognostic value. Patients on larotrectinib had high, sustained ORR, independent of number of prior therapies or duration of adv/met disease, suggesting that the effect of TRK inhibition in molecularly selected patients is independent of prior treatments or disease course.
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http://dx.doi.org/10.1200/PO.21.00089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457788PMC
September 2021

Treatment of 120 adult osteosarcoma patients with metachronous and synchronous metastases: A retrospective series of the French Sarcoma Group.

Int J Cancer 2021 Sep 25. Epub 2021 Sep 25.

Department of Oncology, Hôpital La Timone, Marseille, France.

Treatment options for metastatic osteosarcomas are scarce. Following failure of standard first line therapy, patients who relapse present a challenging treatment dilemma, and have a poor prognosis. Surgical removal of all metastases is essential. A retrospective analysis of patients with metastatic osteosarcomas was conducted in 15 French Sarcoma Group centers. From January 2009 to December 2018, we identified 120 adult patients; 36 with synchronous and 84 with metachronous metastases with 74 males and 46 females. Mean age was 30 years (18-53). Metastatic sites were lung, bone and other in 91, 11 and 24 patients, respectively. Mean time to first metachronous metastases was 22 months (4-97). All patients except 13 (10.8%) with metachronous metastases received a first line systemic treatment for relapse, and 39 patients (32.5%) were included in a clinical trial. Eighty-one patients (67.5%) had local treatment of distant metastases. Median progression free survival (PFS) and overall survival (OS) were 5.5 (95% CI 4.6-6.4) and 20.5 months (95% CI 13.2-27.7) respectively for the overall group. In multivariate analysis, more than five metastases, time to first metastases <24 months, were statistically significant negative prognostic factors for OS and PFS (P = .002, ≤.001 and P = .006, ≤.001, respectively). Surgery of metastases was associated with better prognosis on OS and PFS (P = .001 and .037, respectively). The presence of bone metastases was a negative prognostic factor on OS but not on PFS (P = .021). In reference sarcoma centers, relapsed osteosarcoma patients with more than one metastasis commonly receive more than one line of systemic therapy, and are included in clinical trial if available.
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http://dx.doi.org/10.1002/ijc.33823DOI Listing
September 2021

Implementing a Machine Learning Strategy to Predict Pathologic Response in Patients With Soft Tissue Sarcomas Treated With Neoadjuvant Chemotherapy.

JCO Clin Cancer Inform 2021 Sep;5:958-972

Bordeaux University, Bordeaux, France.

Purpose: Neoadjuvant chemotherapy (NAC) has been increasingly used in patients with locally advanced high-risk soft tissue sarcomas in the past decade, but definition and prognostic impact of a good histologic response (GHR) are lacking. Our aim was to investigate which histologic feature from the post-NAC surgical specimen independently correlated with metastatic relapse-free survival (MFS) in combination with clinical, radiologic, and pathologic features using a machine learning approach.

Methods: This retrospective study included 175 consecutive patients (median age: 59 years, 75 women) with resectable disease, treated with anthracycline-based NAC between 1989 and 2015 in our sarcoma reference center, and with quantitative histopathologic analysis of the surgical specimen. The outcome of interest was the MFS. A multimodel, multivariate survival analysis was used to define GHR. The added prognostic value of GHR was investigated through the comparisons with the standard model (including histologic grade, size, and depth) and SARCULATOR nomogram using concordance indices (c-index) and Monte-Carlo cross-validation.

Results: Seventy-two patients (72 of 175, 41.1%) had a metastatic relapse. Stepwise Cox regression, random survival forests, and least absolute shrinkage and selection operator-penalized Cox regression all converged toward the same definition for GHR, ie, < 5% stainable tumor cells. The five-year MFS probability was 1 (95% CI, 1 to 1) in patients with GHR versus 0.73 (95% CI, 0.65 to 0.81) in patients without GHR (log-rank = .0122). The final prognostic model incorporating the GHR was significantly better than the standard model and SARCULATOR (average c-index in testing sets = 0.72 [95% CI, 0.61 to 0.82] 0.57 [95% CI, 0.44 to 0.70] and 0.54 [95% CI, 0.45 to 0.64], respectively; = .0414 and .0091).

Conclusion: Histologic response to NAC improves the prediction of MFS in patients with soft tissue sarcoma and represents a possible end point in future studies exploring innovative regimens in the neoadjuvant setting.
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http://dx.doi.org/10.1200/CCI.21.00062DOI Listing
September 2021

Safety and antitumor activity of α-PD-L1 antibody as monotherapy or in combination with α-TIM-3 antibody in patients with microsatellite instability-high/mismatch repair-deficient tumors.

Clin Cancer Res 2021 Aug 31. Epub 2021 Aug 31.

Department of Internal Medicine, Seoul National University College of Medicine.

Purpose: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability-high/mismatch repair-deficient (MSI‑H/dMMR) tumors. However, 50 to 60% do not respond to single-agent anti-PD‑1/PD-L1 antibodies, and approximately 50% of responders relapse within 6 to12 months. This phase 1b trial evaluated safety and antitumor activity of anti-PD-L1 antibody LY3300054 monotherapy or in combination with anti-TIM-3 antibody LY3321367 in patients with MSI‑H/dMMR advanced solid tumors.

Experimental Design: Eligible patients {greater than or equal to}18 years without prior anti-PD‑1/PD‑L1 therapy received LY3300054 monotherapy (=40) or combination (=20); patients with PD-1/PD-L1 inhibitor-resistant/refractory tumors received the combination (=22). LY3300054 (700 mg) and anti-TIM-3 antibody (Cycles 1-2: 1200mg, Cycle 3 onwards: 600mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability.

Results: Eighty-two patients were enrolled. Most had colorectal (=39, 47.6%) or endometrial (=14, 17.1%) tumors. >70% of patients in the PD‑1/PD-L1 inhibitor-resistant/refractory combination cohort had received {greater than or equal to}3 treatment lines. Treatment-related adverse events (TRAEs) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD‑1/PD-L1 inhibitor-naïve combination cohort, and 6 (27.3%) in the PD‑1/PD-L1 inhibitor-resistant/refractory combination cohort. 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade {greater than or equal to}3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD‑1/PD-L1 inhibitor-naive combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort.

Conclusions: LY3300054 monotherapy and combined LY3300054/anti-TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor-naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor-resistant/refractory MSI‑H/dMMR tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0261DOI Listing
August 2021

Long-term efficacy update of crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumour from EORTC trial 90101 CREATE.

Eur J Cancer 2021 Oct 13;156:12-23. Epub 2021 Aug 13.

Sarcoma Unit, Mannheim University Medical Center, University of Heidelberg, Mannheim, Germany.

Purpose: European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II basket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up.

Patients/methods: After central reference pathology, eligible ALK-positive and ALK-negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or systemic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed centrally using immunohistochemistry and fluorescence in situ hybridisation. The primary end-point was the proportion of patients who achieved an objective response (i.e. complete or partial response). If ≥6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful.

Results: At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confidence interval [CI] 34.9-90.1%) in ALK-positive patients and 14.3% (95% CI 0.0-57.9%) in ALK-negative patients. In the ALK-positive and ALK-negative patients, the median progression-free survival was 18.0 months (95% CI 4.0-NE) and 14.3 months (95% CI 1.2-31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2-95.6) and 34.3% (95% CI 4.8-68.5). Safety results were consistent with previously reported data.

Conclusion: These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK-positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses.

Clinical Trial Number: EORTC 90101, NCT01524926.
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http://dx.doi.org/10.1016/j.ejca.2021.07.016DOI Listing
October 2021

Safety, pharmacokinetics, and efficacy of budigalimab with rovalpituzumab tesirine in patients with small cell lung cancer.

Cancer Treat Res Commun 2021 25;28:100405. Epub 2021 May 25.

Cancer Care Center, Blacktown Hospital, Sydney, NSW, Australia. Electronic address:

Background: Agents targeting programmed cell death protein 1 (PD-1) have been approved as monotherapy for patients with small cell lung cancer (SCLC). In preclinical models, the combined targeting of PD-1 and delta-like protein 3 resulted in enhanced antitumor activity. Herein, we report results from the expansion arm of study NCT03000257 evaluating the combination of the anti-PD-1 antibody budigalimab and the targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) in patients with previously treated SCLC.

Materials And Methods: This expansion arm of a multicenter, open-label, multi-arm, first-in-human phase 1 clinical trial enrolled adult patients with progressive SCLC. The primary objective was to assess safety and tolerability. Patients received budigalimab 375 mg via intravenous infusion every 3 weeks, and Rova-T was administered as a dose of 0.3 mg/kg intravenously, on day 1 of the first and third 3-week cycle.

Results: As of October 2019, 31 patients with SCLC were enrolled and treated with budigalimab plus Rova-T. The combination was tolerated, with the most common treatment-emergent adverse events (in >30%) being pleural effusion, fatigue, and cough. The overall response rate was 24.1%, with one confirmed complete response and six confirmed partial responses. The overall response rate in patients with high delta-like protein 3 expression was similar (21.1%). The median progression-free survival was 3.48 months.

Conclusion: Combination therapy with budigalimab and Rova-T had promising efficacy and appeared to be tolerated in patients with SCLC. Although Rova-T development has been discontinued, development of budigalimab combined with other anticancer agents is ongoing.

Clinical Trial Registration Number: NCT03000257 Statement on originality of the work The manuscript represents original work and has not been submitted for publication elsewhere nor previously published. Statement of prior presentation Data from this study were previously presented at the European Society for Medical Oncology (ESMO) Congress 2019.
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http://dx.doi.org/10.1016/j.ctarc.2021.100405DOI Listing
May 2021

Precision oncology: a clinical and patient perspective.

Future Oncol 2021 Oct 19;17(30):3995-4009. Epub 2021 Jul 19.

C2A, Paris, 75012, France.

Molecular characterization of tumors has shifted cancer treatment strategies away from nonspecific cytotoxic treatment of histology-specific tumors toward targeting of actionable mutations that can be found across multiple cancer types. The development of high-throughput technologies such as next-generation sequencing, combined with decision support applications and availability of patient databases, has provided tools that optimize disease management. Precision oncology has proven success in improving outcomes and quality of life, as well as identifying and overcoming mechanisms of drug resistance and relapse. Addressing challenges that impede its use will improve matching of therapies to patients. Here we review the current status of precision oncology medicine, emphasizing its impact on patients - what they understand about precision oncology medicine and their hopes for the future.
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http://dx.doi.org/10.2217/fon-2021-0688DOI Listing
October 2021

First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma.

Cancer Immunol Immunother 2021 Jul 3. Epub 2021 Jul 3.

START Madrid-FJD, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain.

Background: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016).

Patients And Methods: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments.

Results: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1-617) and 71 days (range, 1-490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1-24.5) in the HNSCC cohort and 19% (90% CI, 9.2-32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7-4.7) and 1.9 months (95% CI, 1.7-3.7) in the HNSCC and NSCLC cohorts.

Conclusions: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing.
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http://dx.doi.org/10.1007/s00262-021-02973-wDOI Listing
July 2021

Phase I study of daily and weekly regimens of the orally administered MDM2 antagonist idasanutlin in patients with advanced tumors.

Invest New Drugs 2021 Dec 28;39(6):1587-1597. Epub 2021 Jun 28.

Princess Margaret Cancer Centre, Toronto, ON, Canada.

Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. TRIAL REGISTRATION: NCT01462175 (ClinicalTrials.gov), October 31, 2011.
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http://dx.doi.org/10.1007/s10637-021-01141-2DOI Listing
December 2021

Sotorasib for Lung Cancers with p.G12C Mutation.

N Engl J Med 2021 06 4;384(25):2371-2381. Epub 2021 Jun 4.

From the University of Texas M.D. Anderson Cancer Center, Houston (F.S.), and U.S. Oncology Research, the Woodlands (A. Spira) - both in Texas; Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine (B.T.L.) and Thoracic Medical Oncology, Perlmutter Cancer Center, New York University (V.V.), New York, and Roswell Park Cancer Institute, Buffalo (G.K.D.) - all in New York; the Queen Elizabeth Hospital and University of Adelaide, Woodville, SA, Australia (T.J.P.); Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne, Cologne (J.W.), the West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen (M.S.), and the German Cancer Consortium, Heidelberg (M.S.) - all in Germany; the Early Phase Trials and Sarcoma Units, Bergonie Cancer Institute, Bordeaux (A.I.), and Gustave Roussy Institute, Villejuif (F.B., B.B.) - both in France; Fox Chase Cancer Center, Philadelphia (H.B.); Kanagawa Cancer Center, Yokohama (T.K.), and the Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka (T.T.) - both in Japan; the Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland (A.C.-F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A. Sacher); Virginia Cancer Specialists, Fairfax (A. Spira); Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore (A. Spira); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); Amgen, Thousand Oaks, CA (A. Anderson, A. Ang, Q.T., O.M., H.H., G.N., G.F.); and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis (R.G.).

Background: Sotorasib showed anticancer activity in patients with p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC).

Methods: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy.

Results: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in , , or .

Conclusions: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
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http://dx.doi.org/10.1056/NEJMoa2103695DOI Listing
June 2021

Targeting the VEGF Pathway in Osteosarcoma.

Cells 2021 05 18;10(5). Epub 2021 May 18.

Sarcoma Group, Gustave Roussy, 94800 Villejuif, France.

Osteosarcoma is the most common primary tumor of the bones affecting mainly young adults. Despite the advances in the field of systemic anticancer therapy, the prognosis of relapsed of metastatic osteosarcoma patients remain dismal with very short survival. However, the better understanding of the pathophysiology of this subtype of sarcoma has led to the identification of new targeted agents with significant activity. In fact, increased angiogenesis plays a major role in the tumor growth and survival of osteosarcoma patients. Several targeted agents have demonstrated a significant anti-tumor activity including multi-kinase inhibitors. In this review, we will discuss the pathophysiology, rationale, and role of targeting angiogenesis via the VEGF pathway in patients with osteosarcoma with emphasis on the published clinical trials and future directions.
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http://dx.doi.org/10.3390/cells10051240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157846PMC
May 2021

Determinants of the access to remote specialised services provided by national sarcoma reference centres.

BMC Cancer 2021 May 29;21(1):631. Epub 2021 May 29.

Lille University Medical School and Centre Oscar Lambret, Lille, France.

Background: Spatial inequalities in cancer management have been evidenced by studies reporting lower quality of care or/and lower survival for patients living in remote or socially deprived areas. NETSARC+ is a national reference network implemented to improve the outcome of sarcoma patients in France since 2010, providing remote access to specialized diagnosis and Multidisciplinary Tumour Board (MTB). The IGéAS research program aims to assess the potential of this innovative organization, with remote management of cancers including rare tumours, to go through geographical barriers usually impeding the optimal management of cancer patients.

Methods: Using the nationwide NETSARC+ databases, the individual, clinical and geographical determinants of the access to sarcoma-specialized diagnosis and MTB were analysed. The IGéAS cohort (n = 20,590) includes all patients living in France with first sarcoma diagnosis between 2011 and 2014. Early access was defined as specialised review performed before 30 days of sampling and as first sarcoma MTB discussion performed before the first surgery.

Results: Some clinical populations are at highest risk of initial management without access to sarcoma specialized services, such as patients with non-GIST visceral sarcoma for diagnosis [OR 1.96, 95% CI 1.78 to 2.15] and MTB discussion [OR 3.56, 95% CI 3.16 to 4.01]. Social deprivation of the municipality is not associated with early access on NETSARC+ remote services. The quintile of patients furthest away from reference centres have lower chances of early access to specialized diagnosis [OR 1.18, 95% CI 1.06 to 1.31] and MTB discussion [OR 1.24, 95% CI 1.10 to 1.40] but this influence of the distance is slight in comparison with clinical factors and previous studies on the access to cancer-specialized facilities.

Conclusions: In the context of national organization driven by reference network, distance to reference centres slightly alters the early access to sarcoma specialized services and social deprivation has no impact on it. The reference networks' organization, designed to improve the access to specialized services and the quality of cancer management, can be considered as an interesting device to reduce social and spatial inequalities in cancer management. The potential of this organization must be confirmed by further studies, including survival analysis.
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http://dx.doi.org/10.1186/s12885-021-08393-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164290PMC
May 2021

ATR Inhibition as an Attractive Therapeutic Resource against Cancer.

Authors:
Antoine Italiano

Cancer Discov 2021 01;11(1):14-16

Early Phase Trials Unit, Institut Bergonié, Bordeaux, France. DITEP, Gustave Roussy, Villejuif, France. University of Bordeaux, Bordeaux, France.

In this issue of , Yap and colleagues demonstrate in a phase I trial enrolling 22 patients diagnosed with advanced solid tumors that BAY 1895344, a new potent and specific ATR inhibitor, is safe and able to induce durable responses in ATM-deficient tumors. This compelling clinical activity paves the way for innovative combination regimens that rely on exploitation of DNA damage response defects in cancer..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1354DOI Listing
January 2021

Efficacy and safety of regorafenib in patients with metastatic or locally advanced chondrosarcoma: Results of a non-comparative, randomised, double-blind, placebo controlled, multicentre phase II study.

Eur J Cancer 2021 06 22;150:108-118. Epub 2021 Apr 22.

Medical Oncology Department, Centre Léon Bérard, Lyon, France.

Background: This multi-cohort trial explored the efficacy and safety of regorafenib for patients with advanced sarcomas of bone origin; this report details the cohort of patients with metastatic or locally advanced chondrosarcoma (CS), progressing after prior chemotherapy.

Patients And Methods: Patients with CS, progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progressive disease. The primary endpoint was progression-free rate (PFR) at 12 weeks. With one-sided α of 0.05, and 80% power, at least 16/24 progression-free patients at 12 weeks were needed for success (P0 = 50%, P1 = 75%).

Results: From September 2014 to February 2019, 46 patients were included in the CS cohort, and 40 patients were evaluable for efficacy: 16 on placebo and 24 on regorafenib. Thirteen patients (54.2%; 95% CI [35.8%-[) were non-progressive at 12 weeks on regorafenib versus 5 (31.3%; 95% CI [13.2%-[);) on placebo. Median PFS was 19.9 weeks on regorafenib, and 8.0 on placebo. Fourteen placebo patients crossed over to regorafenib after progression. The most common grade ≥3 treatment-related adverse events on regorafenib included hypertension (12%), asthenia (8%), thrombocytopenia (8%) and diarrhoea (8%). One episode of fatal liver dysfunction occurred on regorafenib.

Conclusion: Although the primary endpoint was not met statistically in this small randomised cohort, there is modest evidence to suggest that regorafenib might slow disease progression in patients with metastatic CS after the failure of prior chemotherapy.

Clinical Trial Registration: The trial is registered at ClinicalTrials.gov (NCT02389244).
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http://dx.doi.org/10.1016/j.ejca.2021.03.039DOI Listing
June 2021

Systemic therapies in advanced epithelioid haemangioendothelioma: A retrospective international case series from the World Sarcoma Network and a review of literature.

Cancer Med 2021 04 13;10(8):2645-2659. Epub 2021 Mar 13.

Department of Medical Oncology, IRCCS Fondazione Istituto Nazionale Tumori, Milano, Italy.

Background: This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions.

Methods: Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method.

Results: Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported.

Conclusion: Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.
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http://dx.doi.org/10.1002/cam4.3807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026938PMC
April 2021

A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors.

Invest New Drugs 2021 08 8;39(4):1089-1098. Epub 2021 Mar 8.

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas Medical Center/MD Anderson Cancer Center, Houston, TX, 77030, USA.

Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects. I6F-MC-JJCD was a multicenter, nonrandomized, open-label, Phase 1b study with 5 separate, parallel dose-escalations in patients with advanced or metastatic cancer from a variety of solid tumors, followed by a dose-confirmation phase in prespecified tumor types. This manuscript reports on 3 of 5 groups. The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). Secondary objectives included evaluation of safety, tolerability, efficacy, and pharmacokinetics. Patients (N = 63) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 12 patients, mostly gastrointestinal (diarrhea, nausea, vomiting). The maximum-tolerated dose of crenigacestat was 25 mg in Part B (LY3023414), 50 mg in Part C (abemaciclib), and not established in Part A (taladegib) due to toxicities. Patients had at least 1 adverse event (AE) and 75.0-82.6% were ≥ Grade 3 all-causality AEs. No patient had complete or partial response. Disease control rates were 18.8% (Part B) and 26.1% (Part C). The study was terminated before dose confirmation cohorts were triggered. This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016.
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http://dx.doi.org/10.1007/s10637-021-01094-6DOI Listing
August 2021

Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network.

PLoS One 2021 25;16(2):e0246958. Epub 2021 Feb 25.

Department of Biopathology, Institut Claudius Regaud et Institut Universitaire du Cancer de Toulouse-Oncopôle, Toulouse, France.

Background: Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France.

Methods: The nationwide incidence of sarcoma or TIM (2013-2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed.

Results: Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1-0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p<10-6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per.

Conclusions: This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1<106/year) are less likely to be included in clinical trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246958PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906477PMC
August 2021

Regorafenib-Avelumab Combination in Patients with Microsatellite Stable Colorectal Cancer (REGOMUNE): A Single-arm, Open-label, Phase II Trial.

Clin Cancer Res 2021 Apr 25;27(8):2139-2147. Epub 2021 Jan 25.

Early Phase Trials Unit, Institut Bergonié, Bordeaux, France.

Purpose: Regorafenib is synergistic with immune checkpoint inhibition in colorectal cancer preclinical models.

Patients And Methods: This was a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks on/1 week off, 160 mg every day; avelumab 10 mg/kg i.v. was given every 2 weeks, beginning at cycle 1, day 15 until progression or unacceptable toxicity. The primary endpoint was the confirmed objective response rate under treatment, as per RECIST 1.1. The secondary endpoints included a 1-year nonprogression rate, progression-free survival (PFS), and overall survival (OS), safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 day 1.

Results: Forty-eight patients were enrolled in four centers. Forty-three were assessable for efficacy after central radiological review. Best response was stable disease for 23 patients (53.5%) and progressive disease for 17 patients (39.5%). The median PFS and OS were 3.6 months [95% confidence interval (CI), 1.8-5.4] and 10.8 months (95% CI, 5.9-NA), respectively. The most common grade 3 or 4 adverse events were palmar-plantar erythrodysesthesia syndrome ( = 14, 30%), hypertension ( = 11, 23%), and diarrhea ( = 6, 13%). High baseline infiltration by tumor-associated macrophages was significantly associated with adverse PFS (1.8 vs. 3.7 months; = 0.002) and OS (3.7 months vs. not reached; = 0.002). Increased tumor infiltration by CD8 T cells at cycle 2, day 1 as compared with baseline was significantly associated with better outcome.

Conclusions: The combination of regorafenib + avelumab mobilizes antitumor immunity in a subset of patients with microsatellite stable colorectal cancer. Computational pathology through quantification of immune cell infiltration may improve patient selection for further studies investigating this approach.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3416DOI Listing
April 2021

The safety of current pharmacotherapeutic strategies for osteosarcoma.

Expert Opin Drug Saf 2021 Apr 3;20(4):427-438. Epub 2021 Feb 3.

Sarcoma Unit, Institut Bergonié, Bordeaux, France.

: Peri-operative chemotherapy is the backbone of treatment for patients with osteosarcoma. Methotrexate, cisplatinum, doxorubicin and ifosfamide are the main drugs used in chemotherapy regimens used for osteosarcoma.: We have reviewed here the relevant literature related to the incidence and management of acute and late toxicities of systemic treatment used for the management of patients with osteosarcoma.: Early diagnosis and appropriate management of acute and late toxicities of chemotherapy is crucial for an efficient care of osteosarcoma patients. Although the incidence and management of chemotherapy-related acute toxicities are well known by most oncologists, the use of high doses of methotrexate have the potential to cause fatal toxicities and, therefore, needs careful monitoring. Moreover, the diagnosis of late toxicities is more challenging and requires long-term follow-up for an appropriate management.
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http://dx.doi.org/10.1080/14740338.2021.1881060DOI Listing
April 2021

Management of sarcomas in children, adolescents and adults: Interactions in two different age groups under the umbrellas of GSF-GETO and SFCE, with the support of the NETSARC+ network.

Bull Cancer 2021 Feb 14;108(2):163-176. Epub 2021 Jan 14.

Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France. Electronic address:

Sarcomas are a rare heterogeneous group of malignant neoplasms that can arise in almost any anatomic site and any age. Close collaboration among adult and pediatric cancer specialists in the management of these tumors is of foremost importance. In this review, we present the current multidisciplinary organization in care of patients with sarcoma in France and we review the main advances made in the last decades in systemic and radiotherapy treatment in the main sarcoma types diagnosed in children, adolescents and young adults (AYA), thanks to the international collaboration.
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http://dx.doi.org/10.1016/j.bulcan.2020.10.009DOI Listing
February 2021

New insights into the clinical management of advanced gastrointestinal stromal tumors.

Authors:
Antoine Italiano

Expert Opin Pharmacother 2021 Mar 14;22(4):439-447. Epub 2020 Dec 14.

Department of Medicine, Bergonié Institute, Bordeaux.

Introduction: 90% of gastrointestinal stromal tumors (GISTs) harbor an activating mutation in the or oncogene, and these are known to confer imatinib sensitivity.

Areas Covered: The author reviews the data regarding the current management of GIST, mechanisms of resistance to imatinib, and new drugs currently in clinical development and provides his unique perspectives on the subject matter.

Expert Opinion: Several studies have shown that the response to imatinib in GIST patients mainly depends on the mutational status of or . Moreover, most, if not all, patients treated with imatinib for advanced GIST will develop a secondary progressive disease under the treatment. In most cases, such progressions are the result of acquired resistance due to the occurrence of secondary mutations, especially in GISTs with primary exon 11 mutations. Sunitinib and regorafenib are inhibitors of multiple tyrosine kinases, including KIT, PDGFRα, PDGFRβ, and VEGFRs, and are approved for the management of imatinib- and imatinib/sunitinib-refractory GIST patients, respectively. Clearly, better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors such as avapritinib and ripretinib will provide new individualized therapeutic strategies for GIST patients.
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http://dx.doi.org/10.1080/14656566.2020.1828346DOI Listing
March 2021

Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma.

Cancers (Basel) 2020 Dec 4;12(12). Epub 2020 Dec 4.

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm UMR1037, 31059 Toulouse, France.

Hepatotoxicity is an important concern for nearly 40% of the patients treated with trabectedin for advanced soft tissue sarcoma (ASTS). The mechanisms underlying these liver damages have not yet been elucidated but they have been suggested to be related to the production of reactive metabolites. The aim of this pharmacogenetic study was to identify genetic variants of pharmacokinetic genes such as CYP450 and ABC drug transporters that could impair the trabectedin metabolism in hepatocytes. Sixty-three patients with ASTS from the TSAR clinical trial (NCT02672527) were genotyped by next-generation sequencing for 11 genes, and genotype-toxicity association analyses were performed with R package SNPassoc. Among the results, c.1249A allele (rs2273697) and intron variant c.-15994T (rs7699188) were associated with an increased risk of severe cytolysis, whereas c.3563A allele had a protective effect, as well as variants rs2032582 and rs1128503 (-value < 0.05). Furthermore, *1 rs776746 (c.6986A > G) increased the risk of severe overall hepatotoxicity ( = 0.012, odds ratio (OR) = 5.75), suggesting the implication of metabolites in the hepatotoxicity. However, these results did not remain significant after multiple analysis correction. These findings need to be validated on larger cohorts of patients, with mechanistic studies potentially being able to validate the functional consequences of these variants.
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http://dx.doi.org/10.3390/cancers12123647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761985PMC
December 2020

Phase I/IIa, open-label, multicentre study to evaluate the optimal dosing and safety of ODM-203 in patients with advanced or metastatic solid tumours.

ESMO Open 2020 12;5(6):e001081

Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.

Background: Genetic alterations in fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) signalling are observed in various tumours. We report a first-in-human phase I/IIa trial evaluating tolerability, pharmacokinetics and preliminary antitumour activity of ODM-203, a novel FGFR and VEGFR inhibitor.

Methods: Open-label, non-randomised, multicentre, phase I/IIa dose escalation and expansion study in patients with advanced or metastatic solid tumours.

Results: Overall, 84 patients received treatment; optimal tablet dose was found to be 400 mg/day with food. All patients experienced at least one adverse event; the majority (89.2%) were grade 1 or 2% and 70.4% were considered treatment related. The most commonly reported events were bilirubin increase-related events (75%) and diarrhoea (50%).Overall response rate was 9.2% and median progression-free survival was 16.1 and 12.4 weeks for patients with aberrant or non-aberrant FGFR tumours. Median time on treatment was 10.1 weeks for all patients and 14.5 weeks for patients who received 400 mg tablets.

Conclusion: This study suggests ODM-203 400 mg/day results in sufficient plasma concentrations and acceptable tolerability in most patients. Preliminary signs of therapeutic activity of ODM-203 in patients with solid tumours was observed.

Trial Registration Number: NCT02264418.
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http://dx.doi.org/10.1136/esmoopen-2020-001081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709506PMC
December 2020

High throughput profiling of undifferentiated pleomorphic sarcomas identifies two main subgroups with distinct immune profile, clinical outcome and sensitivity to targeted therapies.

EBioMedicine 2020 Dec 28;62:103131. Epub 2020 Nov 28.

Medical Oncology Department, Institut Bergonié, Bordeaux, France; University of Bordeaux, Bordeaux, France; INSERM U1218, Bordeaux, France. Electronic address:

Background: Undifferentiated pleomorphic sarcoma (UPS) is the most frequent, aggressive and less-characterized sarcoma subtype. This study aims to assess UPS molecular characteristics and identify specific therapeutic targets.

Methods: High-throughput technologies encompassing immunohistochemistry, RNA-sequencing, whole exome-sequencing, mass spectrometry, as well as radiomics were used to characterize three independent cohorts of 110, 25 and 41 UPS selected after histological review performed by an expert pathologist. Correlations were made with clinical outcome. Cell lines and xenografts were derived from human samples for functional experiments.

Findings: CD8 positive cell density was independently associated with metastatic behavior and prognosis. RNA-sequencing identified two main groups: the group A, enriched in genes involved in development and stemness, including FGFR2, and the group B, strongly enriched in genes involved in immunity. Immune infiltrate patterns on tumor samples were highly predictive of gene expression classification, leading to call the group B 'immune-high' and the group A 'immune-low'. This molecular classification and its prognostic impact were confirmed on an independent cohort of UPS from TCGA. Copy numbers alterations were significantly more frequent in immune-low UPS. Proteomic analysis identified two main proteomic groups that highly correlated with the two main transcriptomic groups. A set of nine radiomic features from conventional MRI sequences provided the basis for a radiomics signature that could select immune-high UPS on their pre-therapeutic imaging. Finally, in vitro and in vivo anti-tumor activity of FGFR inhibitor JNJ-42756493 was selectively shown in cell lines and patient-derived xenograft models derived from immune-low UPS.

Interpretation: Two main disease entities of UPS, with distinct immune phenotypes, prognosis, molecular features and MRI textures, as well as differential sensitivity to specific anticancer agents were identified. Immune-high UPS may be the best candidates for immune checkpoint inhibitors, whereas this study provides rational for assessing FGFR inhibition in immune-low UPS.

Funding: This work was partly founded by a grant from La Ligue.
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http://dx.doi.org/10.1016/j.ebiom.2020.103131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708794PMC
December 2020

Safety and Clinical Activity of a New Anti-PD-L1 Antibody as Monotherapy or Combined with Targeted Therapy in Advanced Solid Tumors: The PACT Phase Ia/Ib Trial.

Clin Cancer Res 2021 03 23;27(5):1267-1277. Epub 2020 Nov 23.

Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.

Purpose: This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334).

Patients And Methods: Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy ( = 15) or combined with ramucirumab ( = 10), abemaciclib ( = 24), or merestinib ( = 12). The phase Ib dose expansion enrolled 8 patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety.

Results: Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months.

Conclusions: LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2821DOI Listing
March 2021

Selective Oral MEK1/2 Inhibitor Pimasertib in Metastatic Melanoma: Antitumor Activity in a Phase I, Dose-Escalation Trial.

Target Oncol 2021 01;16(1):47-57

Clinical Research Unit, Institut Universitaire du Cancer, Oncopole, Toulouse, France.

Background: Pimasertib is a selective, potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor.

Objectives: The aim of this study was to describe the efficacy, safety, and pharmacodynamics of pimasertib at pharmacologically active doses in a cohort of patients with locally advanced/metastatic melanoma from a first-in-human study of pimasertib.

Methods: This was a phase I, open-label, two-part, dose-escalation study. Part 1 was conducted in patients with solid tumors and identified the maximum tolerated dose, while Part 2 was restricted to patients with advanced/metastatic melanoma. Endpoints included safety, pharmacodynamics, and antitumor activity. We present data for patients with melanoma only from both parts of the study.

Results: In total, 93 patients with melanoma received pimasertib, 89 of whom received pharmacologically active doses (28-255 mg/day) across four dose regimens in the two parts of the study. The objective response rate was 12.4% (11/89): complete response (n = 1) and partial response (PR; n = 10). Six patients responded for > 24 weeks. Nine of the 11 responders had tumors with B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF; n = 6) and/or NRAS Proto-Oncogene, GTPase (NRAS; n = 3) mutations. Forty-six patients had stable disease (SD). In patients with ocular melanoma (n = 13), best overall response was PR (n = 1), SD (n = 11), and disease progression (n = 1). Phosphorylated extracellular signal-regulated kinase (pERK) levels were substantially reduced within 2 h of treatment and inhibition was sustained with continuous twice-daily dosing. Treatment-related, recurrent, grade 3 or higher adverse events were reported in eight patients, including diarrhea, and skin and ocular events.

Conclusion: Results from this phase I study indicate that pimasertib has clinical activity in patients with locally advanced/metastatic melanoma, particularly BRAF- and NRAS-mutated tumors, at clinically relevant doses associated with pERK inhibition in peripheral blood mononuclear cells.

Trial Registration: ClinicalTrials.gov, NCT00982865.
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http://dx.doi.org/10.1007/s11523-020-00767-1DOI Listing
January 2021

Selective Oral MEK1/2 Inhibitor Pimasertib: A Phase I Trial in Patients with Advanced Solid Tumors.

Target Oncol 2021 01;16(1):37-46

Paris Diderot University Hospital, Clichy, France.

Background: The Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK) signaling cascade is frequently constitutively activated in human cancers. Pimasertib is a selective and potent adenosine triphosphate non-competitive MEK1/2 inhibitor.

Objective: Our objectives were to describe the results of a phase I, first-in-human, dose-escalation trial of pimasertib that investigated the maximum tolerated dose, recommended phase II dose, and safety, as well as other endpoints.

Patients And Methods: Four dosing schedules of pimasertib (once daily [qd], 5 days on, 2 days off; qd, 15 days on, 6 days off; continuous qd; continuous twice daily [bid]) were evaluated in patients with advanced solid tumors. Each treatment cycle lasted 21 days. The primary objective was to determine the maximum tolerated dose based on dose-limiting toxicities (DLTs) evaluated during cycle 1, and the recommended phase II dose (RP2D). Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and antitumor activity.

Results: Overall, 180 patients received pimasertib (dose range 1-255 mg/day). DLTs were mainly observed at doses ≥ 120 mg/day and included skin rash/acneiform dermatitis and ocular events, such as serous retinal detachment. The most common drug-related adverse events were consistent with class effects, including diarrhea, skin disorders, ocular disorders, asthenia/fatigue, and peripheral edema. The median time to maximum pimasertib concentration was 1.5 h across dosing schedules, and the apparent terminal half-life was 5 h across qd dosing schedules. Pimasertib decreased ERK phosphorylation within 2 h of administration, which was maintained for up to 8 h at higher doses and prolonged with bid dosing.

Conclusions: Based on the safety profile and efficacy signals, a continuous bid regimen was the preferred dosing schedule and the RP2D was defined as 60 mg bid.

Trial Registration: ClinicalTrials.gov, NCT00982865.
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http://dx.doi.org/10.1007/s11523-020-00768-0DOI Listing
January 2021

Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour.

Eur J Cancer 2020 12 5;141:162-170. Epub 2020 Nov 5.

Institut Claudius Regaud, Département D'Oncologie Médicale, Toulouse, France.

Objectives: This study investigated the safety, clinical activity and patient-reported outcomes of patients with diffuse-type tenosynovial giant-cell tumour (dTGCT) of the soft tissue who were treated with emactuzumab, a humanised anti-colony stimulating factor 1 receptor (CSF1R) monoclonal antibody and were followed up for up to 2 years after the start of treatment.

Methods: In this open-label phase 1 study (ClinicalTrials.govNCT01494688), patients received intravenous (IV) emactuzumab from 900 to 2000 mg every two weeks in the dose-escalation phase and at the optimal biological dose of 1000 mg with different schedules in the dose-expansion phase. Adverse event (AE) rates and biomarker assessments from tumour biopsies were analysed. Quality of life was assessed using a standard questionnaire (EuroQol-5D-3L) and the WOMAC® 3.1 Osteoarthritis Index. Tumour responses were determined with magnetic resonance imaging.

Results: Altogether, 63 patients were enrolled into the study. The most frequently reported AEs were pruritus, asthenia and oedema. In 36 patients for whom biopsy tissue was available a substantial decrease of CSF1R-positive and CD68/CD163-positive macrophages was detected. The independently reviewed best overall objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors version 1.1) was 71%. Responses were durable, and an ORR of 70% and 64% was determined after one or two years after enrolment into the study. Clinical activity was accompanied by an improvement in EuroQol-5D-3L and particularly the joint disorder-specific WOMAC score.

Conclusions: Systemic therapy of dTGCT patients with emactuzumab resulted in pronounced and durable responses associated with symptomatic improvement and a manageable safety profile.
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http://dx.doi.org/10.1016/j.ejca.2020.09.038DOI Listing
December 2020
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