Abstract Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).
Abstract Introduction: The Cetuximab After Progression in KRAS wild type colorectal cancer patients (CAPRI) study enrolled KRAS exon 2 wild-type (wt) metastatic colorectal cancer (mCRC) patients who received first-line FOLFIRI-cetuximab. Retrospective analysis showed that mCRC patients with KRAS/NRAS/BRAF/PIK3CA wt (quadruple-wt) tumors had an excellent prognosis when treated with anti-EGFR agents. In order to identify additional mechanisms that might allow to better select patients who benefit of anti-EGFR monoclonal antibodies, we analyzed quadruple-wt tumors from the CAPRI clinical trial with a large targeted sequencing panel and correlated results with patients' outcome. Materials and methods: NGS analysis was performed using the Oncomine Comprehensive v.2 panel from Thermofisher on Ion Torrent PGM. The panel covers 143 cancer genes providing information on hotspot mutations of 73 oncogenes, copy number variation (CNV) of 49 genes, full-length sequence of 26 tumor suppressor genes, and sequence of 22 fusion driver genes. Data analysis was carried out using Ion Reporter™ Software v5.0. Results: Complete data of the first cohort of 17 patients are summarized. These patients had a median progression-free survival (mPFS) of 12,3 months (m) and median overall survival (mOS) of 34,03 mos. The analysis revealed in all 17 tumors the presence of at least one mutation, and in 9/17 showed the presence of at least one CNV. Variants were detected in the following genes: TP53 (17 mutations), APC (16), FBXW7 (2), MAP2K1 (1), PTPN11 (1), PTCH1 (1), ATM (1), CTNNB1 (1), PIK3R1 (1), PTEN (1), CDKN2A (1), KRAS (1). CNVs were found in APC (2 deletions), TP53 (1 deletion), PIK3R1 (1 deletion), BCL2L1 (4 amplifications), GAS6 (3 amplifications), MYC (2 amplifications), ZNF217 (2 amplifications), FLT3 (1 amplification), ERBB2 (1 amplification), APEX 1 (1 amplification). The 3 patients with the shortest PFS and OS had peculiar genetic alterations that might be associated with resistance to EGFR targeting drugs. Case #980 (PFS 3,93 m; OS 9,2 m) carried a KRAS p.Gln61His variant at a low allelic frequency (0,38%) that was confirmed by plasma testing with BEAMing. Case #4120 (PFS 5,77 m; OS 25,33 m) had a loss of function PTCH1 variant (p.Tyr1316fs) leading to activation of the sonic hedgehog (SHH) pathway. Case #1491 (PFS 6,63 m; OS 19,03 m) carried a p.Lys57Glu mutations in the MAP2K1 gene that causes constitutive activation of the corresponding protein. Conclusions: These preliminary data show that quadruple-wt CRC carry genetic alterations that potentially can drive resistance to anti-EGFR monoclonal antibodies. While the significance of the identified variants needs to be explored in experimental models, these findings do suggest that wide genetic profiling of CRC might improve our ability to select patients who are highly sensitive to EGFR inhibition. Citation Format: Anna Maria Rachiglio, Matilde Lambiase, Francesca Fenizia, Alessia Iannaccone, Cristin Roma, Claudia Cardone, Antonella De Luca, Erika Martinelli, Evaristo Maiello, Fortunato Ciardiello, Nicola Normanno. Genetic landscape of KRAS-NRAS-BRAF-PIK3CA wild type metastatic colorectal cancer patients enrolled in the CAPRI clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2619.
Rechallenge therapy with anti-epidermal growth factor receptor (EGFR) drugs has been suggested in patients with chemo-refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC) after initial response to anti-EGFR-based first-line treatment. The association of treatment with cetuximab plus avelumab with overall survival (OS) may be worthy of investigation in this setting.To assess the efficacy and safety of cetuximab rechallenge therapy plus avelumab.This single-arm, multicenter phase 2 trial enrolled patients from August 2018 to February 2020. Eligible patients with RAS WT mCRC had a complete or partial response to first-line chemotherapy plus anti-EGFR drugs, developed acquired resistance, and failed second-line therapy. Baseline circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R mutation analysis was done.Patients received avelumab (10 mg/kg every 2 weeks) and cetuximab (400 mg/m2 and, subsequently, 250 mg/m2 weekly) until disease progression or unacceptable toxic effects.The primary end point was OS. Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety.Seventy-seven patients were enrolled (42 men, 35 women; median age, 63 years); 71 had microsatellite stable tumors (MSS), 3 microsatellite instability-high tumors (MSI-H), 3 unknown. The study met the primary end point, with median OS (mOS) of 11.6 months (95% CI, 8.4-14.8 months). Median PFS (mPFS) was 3.6 months (95% CI, 3.2-4.1 months). Common grade-3 adverse events were cutaneous eruption, 11 (14%), and diarrhea, 3 (4%). For 67 of 77 (87%) patients, baseline analysis of plasma circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R variations was feasible. Forty-eight patients had WT disease, whereas 19 had mutations. Patients with RAS/BRAF WT ctDNA had mOS of 17.3 months (95% CI, 12.5-22.0 months) compared with 10.4 months (95% CI, 7.2-13.6 months) in patients with mutated ctDNA (hazard ratio [HR], 0.49; 95% CI, 0.27-0.90; P = .02). The mPFS was 4.1 months (95% CI, 2.9-5.2 months) in RAS/BRAF WT patients compared with 3.0 months (95% CI, 2.6-3.5 months) in patients with mutated ctDNA (HR, 0.42; 95% CI, 0.23-0.75; P = .004).The findings of this single-arm phase 2 trial suggest that cetuximab plus avelumab is an active, well tolerated rechallenge therapy in RAS WT mCRC. Plasma ctDNA analysis before treatment may allow selection of patients who could benefit.ClinicalTrials.gov Identifier: NCT04561336.
•Optimize the access of new innovative drugs to the Italian market.•Methodological tool for new drug’s priority status assessment partially based on that used by the AIFA.•An SPA has been carried out based on three dimensions: UMN, AB and QE. BackgroundWith the rapid development of innovative anticancer treatments, the optimization of tools able to accelerate the access of new drugs to the market by the regulatory authority is a major issue. The aim of the project was to propose a reliable methodological pathway for the assessment of clinical value of new therapeutic innovative options, to objectively identify drugs which deserve early access (EA) priority for solid and possibly in other cancer scenarios, such as the hematological ones.Materials and methodsAfter a comprehensive review of the European Public Assessment Report of 21 drugs, to which innovation had previously been attributed by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), an expert panel formulated an algorithm for the balanced use of three parameters: Unmet Medical Need (UMN) according to AIFA criteria, Added Benefit (AB) according to the European Society for Medical Oncology’s Magnitude of Clinical Benefit Scale (ESMO-MCBS) criteria and Quality of Evidence (QE) assessed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method. By sequentially combining the above indicators, a final priority status (i.e. EA or not) was obtained using the skip pattern approach (SPA).ResultsBy applying the SPA to the non-curative setting in solid cancers, the EA status was obtained by 5 out of 14 investigated drugs (36%); by enhancing the role of some categories of the UMN, additional 4 drugs, for a total of 9 (64%), reached the EA status: 2 and 3 drugs were excluded for not achieving an adequate score according to AB and QE criteria, respectively. For hematology cancer, only the UMN criteria were found to be adequate.ConclusionsThe use of this model may represent a reliable tool for assessment available to the various stakeholders involved in the EA process and may help regulatory agencies in a more comprehensive and objective definition of new treatments’ value in these contexts. Its generalizability in other national contexts needs further evaluation. With the rapid development of innovative anticancer treatments, the optimization of tools able to accelerate the access of new drugs to the market by the regulatory authority is a major issue. The aim of the project was to propose a reliable methodological pathway for the assessment of clinical value of new therapeutic innovative options, to objectively identify drugs which deserve early access (EA) priority for solid and possibly in other cancer scenarios, such as the hematological ones. After a comprehensive review of the European Public Assessment Report of 21 drugs, to which innovation had previously been attributed by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), an expert panel formulated an algorithm for the balanced use of three parameters: Unmet Medical Need (UMN) according to AIFA criteria, Added Benefit (AB) according to the European Society for Medical Oncology’s Magnitude of Clinical Benefit Scale (ESMO-MCBS) criteria and Quality of Evidence (QE) assessed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method. By sequentially combining the above indicators, a final priority status (i.e. EA or not) was obtained using the skip pattern approach (SPA). By applying the SPA to the non-curative setting in solid cancers, the EA status was obtained by 5 out of 14 investigated drugs (36%); by enhancing the role of some categories of the UMN, additional 4 drugs, for a total of 9 (64%), reached the EA status: 2 and 3 drugs were excluded for not achieving an adequate score according to AB and QE criteria, respectively. For hematology cancer, only the UMN criteria were found to be adequate. The use of this model may represent a reliable tool for assessment available to the various stakeholders involved in the EA process and may help regulatory agencies in a more comprehensive and objective definition of new treatments’ value in these contexts. Its generalizability in other national contexts needs further evaluation.
Background Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS mutant metastatic colorectal cancer (mCRC). Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in chemorefractory setting. Methods STREAM was an academic, multicenter, single-arm phase 2 trial, evaluating the activity of regorafenib in RAS mutant mCRC, in terms of the rate of patients who were progression-free after 6months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin and bevacizumab. According to Simon’s two-stage design, ≥ 18 patients 6mo-PF were needed in the overall population (N=46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS) and OS. Early metabolic response by [18F]-FDG PET/CT scan was an exploratory endpoint. EudraCT Number:2015-001105-13 Results The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. ORR was 10.9%, Disease Control Rate 54.6%, median (m)PFS 3.6 months (mo) (95%CI 1.9-6.7), mOS 18.9 mo (95%CI 10.3-35.3), mPFS2 (from study entry to subsequent-line progression) was 13.3mo (95%CI=8.4-19.7). Long responders patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade≥3 events occurred in 39.1% patients, mostly hand-foot syndrome (13%), fatigue and hyperbilirubinemia (6.5%). Baseline metabolic assessment was associated with OS in multivariate analysis, while early metabolic response was not associated with clinical outcomes. Conclusion The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [18F]-FDG PET/CT might be useful to select patients with favorable outcome. A chemotherapy-free interval with regorafenib might be worth of further studies as second-line treatment in selected patients with RAS mutant mCRC.
