Panitumumab plus trifluridine/tipiracil as anti-EGFR rechallenge therapy in patients with refractory RAS wild-type metastatic colorectal cancer: Overall survival and subgroup analysis of the randomized phase II VELO trial.

The randomized phase II VELO trial showed that the addition of panitumumab to trifluridine/tipiracil significantly improves progression-free survival (PFS) as compared to trifluridine/tipiracil in third-line therapy in patients with refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC). With longer follow-up, final overall survival results and posttreatment subgroup analysis are presented. Sixty-two patients with refractory RAS WT mCRC were randomly assigned to receive, as third-line therapy, trifluridine/tipiracil alone (arm A) or in combination with panitumumab (arm B). Primary endpoint was PFS; secondary endpoints included overall survival (OS) and overall response rate (ORR). Median OS was 13.1 months (95% CI 9.5-16.7) in arm A compared to 11.6 months (95% CI 6.3-17.0) in arm B (HR: 0.96, 95% CI 0.54-1.71, P = .9). To evaluate the impact of subsequent lines of treatment, subgroup analysis was performed for the 24/30 patients in arm A, that received fourth-line therapy after disease progression. Median PFS was 4.1 months (95% CI 1.44-6.83) for 17 patients treated with anti-EGFR rechallenge as compared to 3.0 months (95% CI 1.61-4.31) for seven patients that received other therapies (HR: 0.29, 95% CI 0.10-0.85, P = .024). Median OS from the start of fourth-line treatment was 13.6 months (95% CI 7.2-20), and 5.1 months (95% CI 1.8-8.3) for patients treated with anti-EGFR rechallenge vs other therapies, respectively (HR: 0.30, 95% CI 0.11-0.81, P = .019). Final results of the VELO trial support the role of anti-EGFR rechallenge in the continuum of care of patients with RAS/BRAF WT mCRC.

Radiomics and machine learning analysis by computed tomography and magnetic resonance imaging in colorectal liver metastases prognostic assessment.

OBJECTIVE: The aim of this study was the evaluation radiomics analysis efficacy performed using computed tomography (CT) and magnetic resonance imaging in the prediction of colorectal liver metastases patterns linked to patient prognosis: tumor growth front; grade; tumor budding; mucinous type. Moreover, the prediction of liver recurrence was also evaluated. METHODS: The retrospective study included an internal and validation dataset; the first was composed by 119 liver metastases from 49 patients while the second consisted to 28 patients with single lesion. Radiomic features were extracted using PyRadiomics. Univariate and multivariate approaches including machine learning algorithms were employed. RESULTS: The best predictor to identify tumor growth was the Wavelet_HLH_glcm_MaximumProbability with an accuracy of 84% and to detect recurrence the best predictor was wavelet_HLH_ngtdm_Complexity with an accuracy of 90%, both extracted by T1-weigthed arterial phase sequence. The best predictor to detect tumor budding was the wavelet_LLH_glcm_Imc1 with an accuracy of 88% and to identify mucinous type was wavelet_LLH_glcm_JointEntropy with an accuracy of 92%, both calculated on T2-weigthed sequence. An increase statistically significant of accuracy (90%) was obtained using a linear weighted combination of 15 predictors extracted by T2-weigthed images to detect tumor front growth. An increase statistically significant of accuracy at 93% was obtained using a linear weighted combination of 11 predictors by the T1-weigthed arterial phase sequence to classify tumor budding. An increase statistically significant of accuracy at 97% was obtained using a linear weighted combination of 16 predictors extracted on CT to detect recurrence. An increase statistically significant of accuracy was obtained in the tumor budding identification considering a K-nearest neighbors and the 11 significant features extracted T1-weigthed arterial phase sequence. CONCLUSIONS: The results confirmed the Radiomics capacity to recognize clinical and histopathological prognostic features that should influence the choice of treatments in colorectal liver metastases patients to obtain a more personalized therapy.

Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial.

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).

EGFR in Tumor-Associated Myeloid Cells Promotes Development of Colorectal Cancer in Mice and Associates With Outcomes of Patients.

BACKGROUND & AIMS: Inhibitors of the epidermal growth factor receptor (EGFR) are the first-line therapy for patients with metastatic colorectal tumors without RAS mutations. However, EGFR inhibitors are ineffective in these patients, and tumor level of EGFR does not associate with response to therapy. We screened human colorectal tumors for EGFR-positive myeloid cells and investigated their association with patient outcome. We also performed studies in mice to evaluate how EGFR expression in tumor cells and myeloid cells contributes to development of colitis-associated cancer and ApcMin-dependent intestinal tumorigenesis. METHODS: We performed immunohistochemical and immunofluorescent analyses of 116 colorectal tumor biopsies to determine levels of EGFR in tumor and stroma; we also collected information on tumor stage and patient features and outcomes. We used the Mann-Whitney U and Kruskal-Wallis tests to correlate tumor levels of EGFR with tumor stage, and the Kaplan-Meier method to estimate patients' median survival time. We performed experiments in mice lacking EGFR in intestinal epithelial cells (Villin-Cre; Egfrf/f and Villin-CreERT2; Egfrf/f mice) or myeloid cells (LysM-Cre; Egfrf/f mice) on a mixed background. These mice were bred with ApcMin/+ mice; colitis-associated cancer and colitis were induced by administration of dextran sodium sulfate (DSS), with or without azoxymethane (AOM), respectively. Villin-CreERT2 was activated in developed tumors by administration of tamoxifen to mice. Littermates that expressed full-length EGFR were used as controls. Intestinal tissues were collected; severity of colitis, numbers and size of tumors, and intestinal barrier integrity were assessed by histologic, immunohistochemical, quantitative reverse transcription polymerase chain reaction, and flow cytometry analyses. RESULTS: We detected EGFR in myeloid cells in the stroma of human colorectal tumors; myeloid cell expression of EGFR associated with tumor metastasis and shorter patient survival time. Mice with deletion of EGFR from myeloid cells formed significantly fewer and smaller tumors than the respective EGFR-expressing controls in an ApcMin/+ background as well as after administration of AOM and DSS. Deletion of EGFR from intestinal epithelial cells did not affect tumor growth. Furthermore, tamoxifen-induced deletion of EGFR from epithelial cells of established intestinal tumors in mice given AOM and DSS did not reduce tumor size. EGFR signaling in myeloid cells promoted activation of STAT3 and expression of survivin in intestinal tumor cells. Mice with deletion of EGFR from myeloid cells developed more severe colitis after DSS administration, characterized by increased intestinal inflammation and intestinal barrier disruption, than control mice or mice with deletion of EGFR from intestinal epithelial cells. EGFR-deficient myeloid cells in the colon of DSS-treated LysM-Cre; Egfrf/f mice had reduced expression of interleukin 6 (IL6), and epithelial STAT3 activation was reduced compared with controls. Administration of recombinant IL6 to LysM-Cre; Egfrf/f mice given DSS protected them from weight loss and restored epithelial proliferation and STAT3 activation, compared with administration of DSS alone to these mice. CONCLUSIONS: Increased expression of EGFR in myeloid cells from the colorectal tumor stroma associates with tumor progression and reduced survival time of patients with metastatic colorectal cancer. Deletion of EGFR from myeloid cells, but not intestinal epithelial cells, protects mice from colitis-induced intestinal cancer and ApcMin-dependent intestinal tumorigenesis. Myeloid cell expression of EGFR increases activation of STAT3 and expression of survivin in intestinal epithelial cells and expression of IL6 in colon tissues. These findings indicate that expression of EGFR by myeloid cells of the colorectal tumor stroma, rather than the cancer cells themselves, contributes to tumor development.

Computed tomography densitometric study of anti-angiogenic effect of regorafenib in colorectal cancer liver metastasis.

AIM: Regorafenib induces radiological changes in liver metastasis among patients with metastatic colorectal cancer (mCRC). The standard criteria used to evaluate solid tumor response (Response Evaluation Criteria in Solid Tumors) may be limited in assessing response to biologic agents with anti-angiogenic action. PATIENTS & METHODS: A total of 67 hepatic lesions in 32 selected patients were analyzed to evaluate tumor attenuation as measured by Hounsfield unit (HU) and size changes. RESULTS: Following two cycles of regorafenib, tumor HU values decreased in the in 73.1% (49/67) of lesions (average HU changes -25.6%) while tumor size increased in 64.2% (43/67) of them (average size changes +25.4%). CONCLUSION: The computed tomography density changes evaluation may be an additional tool, in combination with tumor sizing, to evaluate tumor response in patients treated with regorafenib.

Radiomic Parameters for the Evaluation of Response to Treatment in Metastatic Colorectal Cancer Patients with Liver Metastasis: Findings from the CAVE-GOIM mCRC Phase 2 Trial.

BACKGROUND: CAVE is a single arm, Phase 2 trial, that demonstrated anti-tumor activity of cetuximab rechallenge plus avelumab in patients with RAS wild type (wt) metastatic colorectal cancer (mCRC). OBJECTIVE: We conducted a post hoc analysis to identify potential radiomic biomarkers for patients with CRC liver metastasis (LM). PATIENTS AND METHODS: Patients with LM that could be measured by enhanced contrast phase computed tomography (CT) imaging at baseline and at first response evaluation were included. Multiple texture parameters were extracted with the LifeX Software. Delta-texture (D-TA) variations were calculated by comparing data at baseline and after treatment. RESULTS: Overall, 55/77 patients (71%) had LM; 39 met the inclusion criteria for the current analysis. The D-TA parameters that significantly correlated at univariate analysis with median progression-free survival (mPFS) were EntropyHistogram (p = 0.021), HomogeneityGLCM (p < 0.001) and Dissimilarity GLCM (p = 0.002). At multivariate analysis, only HomogeneityGLCM resulted significant for PFS (p = 0.001). Patients (19/39, 48.7%) with reduction of HomogeneityGLCM experienced better mPFS (4.6 vs 2.9 months; HR 0.45; 95% CI 0.23-0.88; p = 0.021) and median overall survival (mOS) (17.3 vs 6.8 months; HR 0.40, 95% CI 0.21-0.80; p = 0.010). A trend to better mPFS, was also observed in patients with RAS/BRAF wt circulating tumor DNA and reduction of HomogeneityGLCM. Overall survival was significantly better in this subgroup of patients with low HomogeneityGLCM: mOS was 17.8 (95% CI 15.5-20.2) versus 6.8 months (95% CI 3.6-10.0) (HR 0.34, 95% CI 0.14-0.81; p = 0.016). CONCLUSION: Reduction in the D-TA parameter HomogeneityGLCM by radiomic analysis correlates with improved outcomes in patients with LM receiving cetuximab rechallenge plus avelumab therapy. Larger prospective studies are needed to validate and confirm these findings.

[Precision medicine in oncology: what contribution to clinical practice?] / Medicina di precisione in oncologia: quale contributo alla pratica clinica?

The concept of precision medicine refers to strategies that are designed to provide prevention and treatment based on the characteristics of each patient and the disease. One of the fields where the process of personalization has been very successful is oncology. The path between theory and clinical practice is, however, long and might be shortened by switching methodology, diagnostics, data collection and analysis, and placing a focus on patient-centered care.

Career and Professional Development for Young Oncologists.

Young oncologists around the globe face many challenges when it comes to their career and professional development. Aspects such as time management, work-life balance, career progression, and educational opportunities are only some of them. Professional societies have identified these challenges in this professional group and designed programs to tackle them specifically. The importance of this strategy cannot be overstated, as young oncologists, defined by most societies as oncologists under 40 years of age, compose almost 50% of the oncology workforce. On the other hand, recent surveys have shown that many young oncologists are considering alternative career paths due to burnout issues aggravated by the COVID-19 pandemic, on top of all other challenges. The virtual setting that has been forcedly introduced into our professional life has shortened distances between professionals and might have contributed to more accessible access to information and opportunities that some young oncologists could not profit from due to their traveling constraints. On the other hand, this virtual setting has shown us the asymmetries in opportunities for these professionals. Knowledgeable of all this, we summarize in this article some of the career and professional development offers available to all young oncologists, which we consider could help them deal with current and future challenges.

Heterogeneous disease and intermittent treatment in metastatic colorectal cancer: A case report.

Background: Metastatic colorectal cancer is one of the most common causes of cancer death worldwide. RAS and BRAF mutational analyses are strongly recommended before beginning chemotherapy in the metastatic setting for their predictive role for the efficacy of anti-EGFR monoclonal antibodies. In most of cases, mutational status coincides between primary tumor and metastases. In RAS and BRAF wild-type patients treated with anti-EGFRs, after an induction treatment period, recent evidence supports the role of a maintenance treatment with fluoropyrimidines and anti-EGFRs. However, skin toxicity is the most described and limiting side-effect of maintenance. Moreover, it is described that the continuous administration of these monoclonal antibodies leads to an acquired resistance to anti-EGFRs, with subsequent treatment failure. Intermittent strategy with chemotherapy plus anti-EGFR may help maintain treatment efficacy, delaying resistance. Case presentation: In this case report, we describe the case of a RAS-BRAF wild-type elderly patient undergoing first-line chemotherapy with FOLFOX + panitumumab, reporting response of disease on all metastatic sites except for a node. This node, surgically removed, revealed host BRAF V600 mutant clones. After surgery, patient continued chemotherapy with a stop-and-go strategy continuing to benefit from the same drugs after 4 years since diagnosis, and continuing to achieve response when on treatment, avoiding unacceptable anti-EGFR toxicity. This patient, still alive after 6 years since the diagnosis, represents the case of a good synergy between molecular profiling of disease, surgery, and intermittent treatment.

Panitumumab Plus Trifluridine-Tipiracil as Anti-Epidermal Growth Factor Receptor Rechallenge Therapy for Refractory RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial.

Importance: Current third-line therapies for patients with metastatic colorectal cancer (MCRC) have limited efficacy. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors for RAS wild-type (WT) MCRC may be valuable for these patients. Objective: To compare the anti-EGFR monoclonal antibody panitumumab plus standard-of-care trifluridine-tipiracil with trifluridine-tipiracil alone as third-line therapy for RAS WT MCRC. Design, Setting, and Participants: This phase 2 randomized clinical trial (RCT) was conducted in 7 Italian centers from June 2019 to April 2022. Patients with refractory RAS WT MCRC who had a partial or complete response to first-line chemotherapy plus an anti-EGFR monoclonal antibody and an anti-EGFR drug-free interval of 4 or more months during second-line therapy were included. Interventions: Patients were randomized 1:1 to receive panitumumab plus trifluridine-tipiracil or trifluridine-tipiracil alone. Main Outcomes and Measures: The primary end point was progression-free survival (PFS). Circulating tumor DNA (ctDNA) extended sequence variation analysis was performed in a subgroup of patients. Results: Of 62 included patients, 31 received panitumumab plus trifluridine-tipiracil (19 [61.3%] male; median age, 65 years [range, 39-81 years]) and 31 received trifluridine-tipiracil alone (17 [54.8%] male; median age, 66 years [range, 32-82 years]). The primary end point was met. Median PFS was 4.0 months (95% CI, 2.8-5.3 months) in the panitumumab plus trifluridine-tipiracil arm vs 2.5 months (95% CI, 1.4-3.6 months) in the trifluridine-tipiracil only (hazard ratio [HR], 0.48; 95% CI, 0.28-0.82; P = .007). Pretreatment plasma RAS/BRAF WT ctDNA identified patients obtaining prolonged clinical benefit with panitumumab plus trifluridine-tipiracil compared with trifluridine-tipiracil, with PFS rates at 6 months of 38.5% vs 13.0% and at 12 months of 15.4% vs 0%. A ctDNA liquid-biopsy extended mutation analysis by FoundationOne Liquid CDx (profiling 324 genes) was performed in a subgroup of patients with baseline plasma RAS/BRAF WT ctDNA; in 15 of 23 patients (65.2%) whose tumors were WT for KRAS, NRAS, BRAFV600E, EGFR, ERBB2, MAP2K1, and PIK3CA, median PFS was 6.4 months (95% CI, 3.7-9.2 months). Within this group of 15 patients, 2 (13.3%) had partial response, 11 (73.3%) had stable disease, and 2 (13.3%) had disease progression as best response. Conclusions and Relevance: In this RCT, third-line treatment with the anti-EGFR monoclonal antibody panitumumab plus the standard-of-care trifluridine-tipiracil resulted in improved PFS compared with treatment with trifluridine-tipiracil alone among patients with refractory RAS WT MCRC. The findings support the clinical utility of liquid biopsy-guided anti-EGFR rechallenge therapy for refractory RAS WT MCRC. Trial Registration: ClinicalTrials.gov Identifier: NCT05468892.

Pathophysiology and Therapeutic Perspectives for Chemotherapy-induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) develops as a challenging nerve-damaging adverse effect of anticancer drugs used in chemotherapy. The disorder may require a chemotherapy dose reduction and a cessation of administration of chemotherapeutic drugs. Its principal sensory symptoms include, tingling, and numbness in the hands and feet. Severe pain can be encompassed among clinical manifestations. CIPN affects dramatically the patient's quality of life (QoL). Pain and sensory symptoms may occur for months, or even years after the termination of chemotherapeutic drugs. Although many pharmacological and non-pharmacological therapeutic approaches have been tested to overcome these symptoms, there is currently no standardized treatment for CIPN. According to current guidelines, Duloxetine is the only recommended agent for painful neuropathic symptoms. Therefore, finding effective therapies for CIPN is mandatory. The aim of this review was to dissect CIPN, the target and immunotherapy-based approaches to this disorder, as well as to offer new insights for new therapeutic perspectives.

Assessing the benefit of cancer drugs approved by the European Medicines Agency using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale over time.

BACKGROUND: Increasingly, cancer drugs are being approved based on surrogate measurements of efficacy. Clinically meaningful data, such as overall survival (OS) and quality of life, are often only presented in subsequent publications. We examined if the clinical benefit of cancer drugs, as measured by the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), improves post-European Medicines Agency (EMA) approval as more data emerges. METHODS: Cancer drug indications approved by the EMA from January 2006 to December 2016 were reviewed and trials cited for efficacy were identified. Primary and subsequent publications (up to December 2019) of scorable trials were included. Changes in benefit over time were measured using ESMO-MCBS thresholds for non-curative (≥4 for substantial, =3 for intermediate and ≤2 for low benefit) and curative intent (A or B for major benefit) scoring. RESULTS: Fifty-five non-curative and two curative intent trials were included. At approval, 29.1% of non-curative trials were substantial, 45.5% intermediate and 25.5% low benefit. For curative intent trials, one displayed major benefit and one displayed no major benefit. We identified 82 subsequent publications for reassessment. A change in ESMO-MCBS classification was seen in 34.5% of non-curative trials (11 raised and 8 lowered). At 3-year reassessment, 36.4% of non-curative trials were substantial, 34.5% intermediate and 29.1% low benefit. Both curative trials showed no major benefit at reassessment. CONCLUSION: As over a third of trials changed classification, in either direction, reassessing the ESMO-MCBS score of approved cancer drugs may help to inform patients and ensure ongoing relevance of regulatory and reimbursement decisions.

Vulnerability to low-dose combination of irinotecan and niraparib in ATM-mutated colorectal cancer.

BACKGROUND: Despite the advancements in new therapies for colorectal cancer (CRC), chemotherapy still constitutes the mainstay of the medical treatment. For this reason, new strategies to increase the efficacy of chemotherapy are desirable. Poly-ADP-Ribose Polymerase inhibitors (PARPi) have shown to increase the activity of DNA damaging chemotherapeutics used in the treatment of CRC, however previous clinical trials failed to validate these results and pointed out dose-limiting toxicities that hamper the use of such combinations in unselected CRC patients. Nevertheless, in these studies little attention was paid to the mutational status of homologous recombination repair (HRR) genes. METHODS: We tested the combination of the PARPi niraparib with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 molecularly annotated CRC cell lines, encompassing the 4 consensus molecular subtypes (CMSs). Synergism was calculated using the Chou-Talalay method for drug interaction. A correlation between synergism and genetic alterations in genes involved in homologous recombination (HR) repair was performed. We used clonogenic assays, mice xenograft models and patient-derived 3D spheroids to validate the results. The induction of DNA damage was studied by immunofluorescence. RESULTS: We showed that human CRC cell lines, as well as patient-derived 3D spheroids, harboring pathogenic ATM mutations are significantly vulnerable to PARPi/chemotherapy combination at low doses, regardless of consensus molecular subtypes (CMS) and microsatellite status. The strongest synergism was shown for the combination of niraparib with irinotecan, and the presence of ATM mutations was associated to a delay in the resolution of double strand breaks (DSBs) through HRR and DNA damage persistence. CONCLUSIONS: This work demonstrates that a numerically relevant subset of CRCs carrying heterozygous ATM mutations may benefit from the combination treatment with low doses of niraparib and irinotecan, suggesting a new potential approach in the treatment of ATM-mutated CRC, that deserves to be prospectively validated in clinical trials.

Dual inhibition of TGFß and AXL as a novel therapy for human colorectal adenocarcinoma with mesenchymal phenotype.

A subset of colorectal cancer (CRC) with a mesenchymal phenotype (CMS4) displays an aggressive disease, with an increased risk of recurrence after surgery, reduced survival, and resistance to standard treatments. It has been shown that the AXL and TGFß signaling pathways are involved in epithelial-to-mesenchymal transition, migration, metastatic spread, and unresponsiveness to targeted therapies. However, the prognostic role of the combination of these biomarkers and the anti-tumor effect of AXL and TGFß inhibition in CRC still has to be assessed. To evaluate the role of AXL and TGFß as negative biomarker in CRC, we conducted an in-depth in silico analysis of CRC samples derived from the Gene Expression Omnibus. We found that AXL and TGFß receptors are upregulated in CMS4 tumors and are correlated with an increased risk of recurrence after surgery in stage II/III CRC and a reduced overall survival. Moreover, we showed that AXL receptor is differently expressed in human CRC cell lines. Dual treatment with the TGFß galunisertib and the AXL inhibitor, bemcentinib, significantly reduced colony formation and migration capabilities of tumor cells and displayed a strong anti-tumor activity in 3D spheroid cultures derived from patients with advanced CRC. Our work shows that AXL and TGFß receptors identify a subgroup of CRC with a mesenchymal phenotype and correlate with poor prognosis. Dual inhibition of AXL and TGFß could represent a novel therapeutic strategy for patients with this aggressive disease.

Cetuximab Rechallenge Plus Avelumab in Pretreated Patients With RAS Wild-type Metastatic Colorectal Cancer: The Phase 2 Single-Arm Clinical CAVE Trial.

IMPORTANCE: 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. OBJECTIVE: To assess the efficacy and safety of cetuximab rechallenge therapy plus avelumab. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURES: The primary end point was OS. Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04561336.

Resistance to anti-epidermal growth factor receptor in metastatic colorectal cancer: What does still need to be addressed?

Colorectal cancer (CRC) represents a global health problem, being one of the most diagnosed and aggressive tumors. Cetuximab and panitumumab monoclonal antibodies (mAbs) in combination with chemotherapy are an effective strategy for patients with RAS Wild Type (WT) metastatic colorectal cancer (mCRC). However, tumors are often unresponsive or develop resistance. In the last years, molecular alterations in principal oncogenes (RAS, BRAF, PI3KCA, PTEN) in the downstream pathway of the epidermal growth factor receptor (EGFR) and in other receptors (HER2, MET) that converge on MAPK-ERK signalling have been identified as novel mechanisms of resistance to anti-EGFR strategies. However, further efforts are needed to better stratify CRCs and ensure more individualized treatments. Herein, we describe the consolidated molecular drivers of resistance and the therapeutic strategies available so far, with an overview on potential biomarkers of response that could be integrated in clinical practice.

Cancer care during the spread of coronavirus disease 2019 (COVID-19) in Italy: young oncologists' perspective.

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AXL is a predictor of poor survival and of resistance to anti-EGFR therapy in RAS wild-type metastatic colorectal cancer.

BACKGROUND: RAS mutations are the only validated biomarkers in metastatic colorectal cancer (mCRC) for anti-epidermal growth factor receptor (EGFR) therapy. Limited clinical information is available on AXL expression, marker of epithelial to mesenchymal transition, in mCRC. METHODS: AXL was retrospectively assessed by immunohistochemistry in 307 patients. RAS wild-type (WT) patients (N = 136) received first-line anti-EGFR-based therapy; RAS mutant patients (N = 171) received anti-angiogenic-based regimens. Preclinical experiments were performed using human RAS WT CRC cell lines and xenograft models. AXL RNA levels were assessed in a cohort of patients with available samples at baseline and at progression to anti-EGFR treatment and in the GSE5851 dataset. RESULTS: AXL was expressed in 55/307 tumour tissues, correlating with worse survival in the overall population (AXL-positive, 23.7 months; AXL-negative, 30.8 months; HR, 1.455, P = 0.032) and in RAS WT patients (AXL-positive, 23.0 months; AXL-negative, 35.8 months; HR,1.780, P = 0.032). Progression-free survival (PFS) in the RAS WT cohort was shorter in the AXL-positive cohort (6.2 months versus 12.1 months; HR, 1.796, P = 0.013). Three-dimensional cultures obtained from a patient following anti-EGFR therapy resulted AXL-positive, showing resistance to anti-EGFR drugs and sensitivity to AXL inhibition. AXL transfection in CRC cell lines induced AXL overexpression and resistance to the EGFR blockade. At progression to cetuximab, 2/10 SW48-tumour xenograft mice showed AXL expression. Consistently, AXL RNA levels increased in 5/7 patients following anti-EGFR therapy. Moreover, in the GSE5851 dataset higher AXL RNA levels correlated with worse PFS with cetuximab in KRAS-exon2 WT chemorefractory patients. CONCLUSIONS: AXL is a marker of poor prognosis in mCRC with consistent clinical and preclinical evidences of involvement in primary and acquired resistance to anti-EGFR drugs in RAS WT patients.