Anti-epidermal Growth Factor Receptor Agents Research Articles

First Line Chemotherapy in Metastatic Colorectal Cancers: A Review

Colorectal cancer (CRC) is a common malignancy detected. Approximately, 22% of CRCs are metastatic at initial diagnosis, and about 70% of patients will eventually develop metastatic relapse. Metastatic colorectal cancer is a disease with poor prognosis whose treatment is always palliative chemotherapy. Today, thanks to the knowledge of molecular biology and the discoveries of new pathways, we have managed to increase survival to around 40 months which can increase thanks to the use of surgery and locoregional treatments. The choice of chemotherapy in these patients therefore depends on the characteristics of the molecular profile and includes, in fit patients, chemotherapy with the addition of targeted therapies. In this article, we examine the most recent data from randomized clinical trials supporting the use of chemotherapy triplets or doublets as well as the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents.

Trifluridine-Tipiracil (Lonsurf)


 CADTH recommends that Lonsurf be reimbursed by public drug plans in combination with bevacizumab for the treatment of metastatic colorectal cancer (mCRC) in adults who have been previously treated with or are not candidates for available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies; anti–vascular endothelial growth factor (anti-VEGF) biological agents; and, if positive for RAS wild-type disease, anti-epidermal growth factor receptor (anti-EGFR) agents, if certain conditions are met.
 Lonsurf should be covered for use in adults with histologically confirmed adenocarcinoma that cannot be surgically removed or has spread to other parts of the body and if the patient’s disease progressed or the patient was intolerant to a maximum of 2 prior chemotherapy regimens. Eligible patients should have good overall health (performance status) and no unstable neurologic issues related to the central nervous system (CNS) or need increasing doses of steroids to control CNS disease.
 Lonsurf should be reimbursed in combination with bevacizumab. It should be prescribed by doctors who specialize in diagnosing and treating patients with mCRC. Lonsurf plus bevacizumab should be stopped if the disease worsens or the patient has severe side effects. The cost of Lonsurf should be reduced.

HGCSG1801: A multicenter, prospective, phase II trial of second-line FOLFIRI plus aflibercept in patients with metastatic colorectal cancer (mCRC) refractory to anti-EGFR antibodies.

113 Background: Aflibercept (AFL) combined with FOLFIRI prolongs overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) who failed a prior oxaliplatin-based regimen. However, there is limited evidence on the efficacy and safety of AFL plus FOLFIRI in RAS / BRAF wild type pts previously treated with anti-epidermal growth factor receptor (EGFR) agents. Therefore, we conducted a phase II trial evaluating the efficacy and safety of AFL plus FOLFIRI in Japanese pts with mCRC failing a prior oxaliplatin-based chemotherapy combined with an anti-EGFR agent. Methods: This was a prospective open-label phase II trial. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 iv, bolus 5-FU 400 mg/m2 and infusional 5-FU 2400 mg/m2/46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was progression-free survival (PFS) rate at 6 months; secondary endpoints included OS, PFS, overall response rate (ORR), disease control rate (DCR), adverse events, and relative dose intensity (RDI) for each drug. Given a PFS rate threshold at 6 months of 38.9% and an expected PFS rate of 58.4% with AFL plus FOLFIRI, a sample size of 41 pts was required (two-sided alpha, 0.1; beta, 0.2). Analyses were conducted in the full analysis set (FAS) of pts satisfying eligibility criteria. Results: Forty-three patients were enrolled between November 2019 and October 2022, and 43 were analyzed (median age 68 years (range 27-80); male, 69.8%; ECOG PS 0/1, 72.1%/27.9%; left sided primary tumor, 90.7%). The primary endpoint was met: 6-month PFS rate was 58.7% (90%CI, 45.5%-71.9%). Median PFS and OS were 7.3 months (95%CI, 5.5-11.0 months) and 18.8 months (95%CI, 12.9-26.6 months), respectively. The ORR was 23.3 % (95%CI, 11.8-38.6%) and DCR was 88.4% (95%CI, 74.9- 96.1%). Mean RDI of AFL, irinotecan, bolus 5-FU and infusional 5-FU were 75.3% (SD, 26.2), 50.6% (SD, 12.5), 31.6% (SD, 26.6), and 58.7% (SD, 7.21), respectively. The main grade ≥3 adverse events included hypertension (62.8%), neutropenia (55.8%), leukopenia (25.6%), febrile neutropenia (11.6%), fatigue (9.3%), anorexia (9.3%), proteinuria (9.3%) and diarrhea (7.0%). No deaths and no new safety signals with a causal relation to the study treatment were observed. Conclusions: Results of this prospective phase II study suggest that AFL plus FOLFIRI shows a high response rate and a manageable safety profile in Japanese pts with mCRC who failed a first-line oxaliplatin-based plus anti-EGFR regimen. Clinical trial information: jRCTs011190006 .

Assessing the effectiveness of targeted agents in adjuvant therapy for patients with metastatic colorectal cancer undergoing surgical resection: a retrospective cohort study.

Primary tumor resection and metastasectomy may be beneficial for many patients with metastatic colorectal cancer (mCRC). To assess the differences in postoperative survival outcomes between adjuvant therapy with chemotherapy alone and chemotherapy plus targeted agents (TAs). Retrospective cohort study. Patients with mCRC who underwent surgical resection for primary colorectal tumor and distant metastases and received adjuvant therapy from 1 January 2010 to 31 December 2017 were enrolled in the Taiwan Cancer Registry. We analyzed the overall survival of patients with resectable or initially unresectable mCRC who received adjuvant chemotherapy alone and chemotherapy plus TAs. We enrolled 1124 and 542 patients with resectable and initially unresectable mCRC, respectively. Adjuvant chemotherapy plus TAs and chemotherapy alone resulted in similar mortality rates among patients with resectable mCRC [adjusted hazard ratio (aHR) = 1.13; 95% confidence interval (CI), 0.93-1.36]; however, it marginally reduced the mortality rate among patients with initially unresectable mCRC who underwent conversion surgery after neoadjuvant therapy (aHR = 0.81; 95% CI, 0.62-1.06). The subgroup analysis of patients who received more than nine cycles of TAs preoperatively and anti-epidermal growth factor receptor agents revealed aHRs of 0.48 (95% CI, 0.27-0.87) and 0.33 (95% CI, 0.18-0.60), respectively. Adjuvant chemotherapy plus TAs may improve survival in patients with initially unresectable tumors who underwent conversion surgery following neoadjuvant therapy with TAs, especially in those who respond well to the targeted therapy. Our study underscores the importance of stratifying patients with mCRC based on tumor resectability when selecting the adjuvant therapy regimen.

Progress of research on molecular targeted therapies for colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies, accounting for approximately 10% of global cancer incidence and mortality. Approximately 20% of patients with CRC present metastatic disease (mCRC) at the time of diagnosis. Moreover, up to 50% of patients with localized disease eventually metastasize. mCRC encompasses a complex cascade of reactions involving multiple factors and processes, leading to a diverse array of molecular mechanisms. Improved comprehension of the pathways underlying cancer cell development and proliferation, coupled with the accessibility of relevant targeted agents, has propelled advancements in CRC treatment, ultimately leading to enhanced survival rates. Mutations in various pathways and location of the primary tumor in CRC influences the efficacy of targeted agents. This review summarizes available targeted agents for different CRC pathways, with a focus on recent advances in anti-angiogenic and anti-epidermal growth factor receptor agents, BRAF mutations, and human epidermal growth factor receptor 2-associated targeted agents.

Primary tumour side as a driver for treatment choice in RAS wild-type metastatic colorectal cancer patients: a systematic review and pooled analysis of randomised trials

BackgroundRetrospective subgroup analyses of previous trials in the first-line therapy of RAS wt metastatic colorectal cancer (mCRC) suggested a predictive impact of primary tumour side on the efficacy of anti-epidermal growth factor receptor (EGFR) agents. Recently, new head-to-head trials of doublets/bevacizumab versus doublets/anti-EGFR, PARADIGM and CAIRO5 were presented. Patients and methodsWe searched for phase II and III trials comparing doublet chemotherapy plus an anti-EGFR or bevacizumab as the first-line treatment for RAS wt mCRC patients. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and radical resection rate result in the overall study populations and, according to the primary side, were pooled together in a two-stage analysis with random effects and fixed effect models. The interaction between sidedness and treatment effect was then analysed. ResultsWe identified five trials (PEAK, CALGB/SWOG 80405, FIRE-3, PARADIGM and CAIRO5), including 2739 patients, 77% left- and 23% right-sided. Among patients with left-sided mCRC, the use of anti-EGFRs was associated with higher ORR (74% versus 62%, OR = 1.77 [95% confidence interval {CI} 1.39–2.26–0.88], p < 0.0001), longer OS (hazard ratio [HR] = 0.77 [95% CI 0.68–0.88], p < 0.0001) and not significantly longer PFS (HR = 0.92, p = 0.19). Among patients with right-sided mCRC, the use of bevacizumab was associated with longer PFS (HR = 1.36 [95% CI 1.12–1.65], p = 0.002) and not significantly longer OS (HR = 1.17, p = 0.14). A subgroup analysis confirmed a significant interaction effect between the primary tumour side and treatment arm in terms of ORR (p = 0.02), PFS (p = 0.0004) and OS (p = 0.001). No differences in the radical resection rate were found according to treatment and sidedness. ConclusionsOur updated metanalysis corroborates the role of the primary tumour location in the choice of the upfront therapy for RAS wt mCRC patients, leading to strongly recommend anti-EGFRs in left-sided tumours and to prefer bevacizumab in the right-sided.

STRATEGIC-1: Multi-line therapy trial in unresectable wild-type KRAS/NRAS/BRAF metastatic colorectal cancer—A GERCOR-PRODIGE randomized open-label phase III study.

3504 Background: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic and anti-epidermal growth factor receptor (EGFR) agents have become available. Ultimately, strategy trials are needed to define the optimal use and the best sequencing of these agents. Methods: Patients with previously untreated RAS/BRAF wild-type unresectable mCRC were randomly assigned (1:1 ratio) to receive either FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab (arm A) or OPTIMOX-bevacizumab followed by FOLFIRI-bevacizumab followed by EGFR mab +/- irinotecan (arm B). This trial was designed as a superiority study (hypothesis arm B &gt; arm A) with Duration of Disease Control (DDC) as primary endpoint, defined as the sum of PFS of each active sequence of treatment (Chibaudel B, J Clin Oncol, 2011). Secondary endpoints were overall survival (OS), Time to Failure of Strategy (TFS), Progression-free survival (PFS) and response rate (RECIST version 1.1) per sequence, salvage surgery rate, safety, and Quality of life (QoL). Results: Between October 2013 and May 2019, 263 eligible patients were randomized (arm A, n = 131; arm B, N = 132). After a median follow-up of 51.2 months (95% CI 43.3-57.4), 188 events for DDC were observed. Efficacy outcomes are presented in table. Median DDC was similar in both arms (HR 0.97, 95% CI 0.72-1.29; P = 0.805). Salvage surgery for metastasis (+/- radiofrequency ablation) was done in 36 (27.5%) patients in arm A and 28 (21.2%) in arm B. Median time until definitive deterioration of QoL (global health status) were 18.3 and 18.0 months (P = 0.628). The safety profiles were consistent with the established safety profiles of each treatment regimen. Conclusions: STRATEGIC-1 is the first randomized phase III study comparing multi-line standard treatment strategies in patients with KRAS/NRAS/BRAF wild-type mCRC. This study did not meet its primary endpoint of DDC. The treatment strategy starting with FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab led to higher response rates and to a trend for better median OS exceeding 3 years. These findings may add to our understanding of treatment sequencing in mCRC. Clinical trial information: NCT01910610. [Table: see text]

Efficacy of anti-epidermal growth factor receptor agents in patients with RAS wild-type metastatic colorectal cancer ≥ 70 years

PurposeColorectal cancer (CRC) affects many older adults. We investigated the efficacy and safety of adding anti-epidermal growth factor receptor (EGFR) agents to doublet chemotherapy (DC) in older patients. MethodsPatients with RAS wild-type (WT) metastatic CRC (mCRC) receiving first-line DC + anti-EGFR (n = 1191) or DC alone (n = 729) from seven trials in the Aide de Recherche en Cancerologie Digestive database were included. The prognostic and predictive effects of age were investigated. Progression-free and overall survival (OS) were evaluated between age groups (≥70 vs <70) for DC + anti-EGFR. In addition, outcomes were compared between DC+/-anti-EGFR within age groups in three trials with a DC alone arm. Subsequently, the same analysis was conducted for left-sided tumours. Adverse events grade ≥3 (G3+) were compared between age groups. ResultsOlder (vs younger) patients receiving DC + anti-EGFR had similar progression-free survival (PFS) (8.7 vs 10.3 months; hazard ratio (HR) = 1.20 [0.96–1.49];p = 0.107) but inferior OS (21.3 vs 26.3; HR = 1.36 [1.08–1.72];p = 0.011). DC + anti-EGFR (vs DC alone) improved OS (23.9 vs 20.3; HR = 0.82 [0.70–0.95];p = 0.008) and PFS (11.2 vs 8.9; HR = 0.70 [0.60–0.82];p < 0.001) in younger but not older patients: OS (24.7 vs 17.6; HR [95% confidence interval {CI}] = 0.77 [0.58–1.04];p = 0.092) and PFS (9.1 vs 8.7; HR [95% CI] = 0.85[0.63–1.15];p = 0.287). In left-sided ‘only’ tumours, the following outcomes for older (vs younger) patients were observed. For DC + anti-EGFR, PFS 9 versus 11.2 months; HR1.10 (95% CI 0.83–1.46); p = 0.52, OS 25.6 vs 30.3 HR 1.32 (95% CI 0.97–1.79), p = 0.086. For DC + anti-EGFR (vs DC alone), PFS and OS for younger patients were 11.9 vs 9.2 months HR 0.60 (95% CI 0.47–0.78) p < 0.001 and 24.1 versus 23.3 months HR 0.84 (95% CI 0.67–1.04), respectively. For older patients, PFS and OS were 13.1 versus 8.5 months, HR 0.51 (95% CI, 0.28–0.93), P = 0.027 and 26.3 versus 16.5 months HR 0.49 (95% CI, 0.28–0.85), respectively. There was no significant difference in toxicity among different age groups. ConclusionsOlder (vs younger) patients with mCRC RAS WT patients had comparable toxicity and efficacy with the addition of anti-EGFR agents to chemotherapy.

A RARE CAUSE OF INTERSTITIAL LUNG DISEASE

TOPIC: Diffuse Lung Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Clinicians should be aware of the potential adverse effects and complications that can occur with molecularly targeted agents for them to be able to diagnose and treat the condition. CASE PRESENTATION: 65-year-old female with stage IV epidermal growth factor receptor (EGFR) lung adenocarcinoma with metastases to the brain, spine, liver, and kidneys undergoing treatment with osimertinib for two months presented with a subjective fever of 102 °F. On admission the patient was tachycardic with an elevated lactate warranting investigation and treatment of sepsis secondary to a UTI. Despite using broad spectrum antibiotics and proper fluid resuscitation, her hospital course was complicated with the development of a new onset dyspnea with exertion and insidious hypoxic respiratory failure. Computed tomography angiography (CTA) of the chest revealed an incidental sub segmental pulmonary embolism which was not treated with anticoagulation due to underlying hemorrhagic brain metastasis. More importantly, the CTA showed new ground glass opacities demonstrated on the upper lung fields concerning for interstitial lung disease (ILD). Osimertinib was discontinued and high-dose IV methylprednisolone was administered resulting in immediate relief of dyspnea and cessation of relapsing fever. There was also a significant improvement to the hypoxia within a 24-hour period. Patient was transitioned to oral prednisone and discharged home the following day. DISCUSSION: Anti-epidermal growth factor receptor agents, a class of small molecule kinase inhibitors, are primarily used for the treatment of advanced non-small cell lung cancer. Common side effects for this particular class of tyrosine kinase inhibitors (TKIs) include fatigue, rashes, and lymphopenia. The risk of ILD for patient's taking EGFR-TKIs is a rare incidence, occurring at a rate of 1-3%, within the first 2-3 months of initiating therapy. The exact mechanism of TKI induced lung injury remains unknown, the proposing theory is an interruption to the alveolar repair mechanism which potentiates lung injury to other causes, such as sepsis, medications, and prior radiation therapy. Discontinuation of EGFR-TKIs therapy is the primary modality to prevent worsening of ILD. Utilization of high-dose glucocorticoids is an additional measure that can be employed for the treatment of drug-induced ILD. CONCLUSIONS: Physicians must be vigilant, with a high degree of clinical suspicion, to discontinue the offending agent in the event that a patient on EGFR-TKIs therapy presents with fever, acute dyspnea with or without cough, tachycardia, and hypoxia. If symptoms of the adverse reaction are not recognized early enough, they may progress to other conditions, such as pulmonary fibrosis. In addition, there is an increased mortality ratewith the continuation of these agents once ILD develops. REFERENCE #1: Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib.Ann Oncol. 2019;30(5):839. DISCLOSURES: No relevant relationships by Ankita Aggarwal, source=Web Response No relevant relationships by Yashar Eshman, source=Web Response no disclosure on file for Mohammad Fityan; No relevant relationships by Victoria Gonzalez, source=Web Response No relevant relationships by Zain Kulairi, source=Web Response

459P Dynamic changes of pro-angiogenic factors during FOLFIRI-aflibercept treatment: Interim analysis of DISTINCTIVE trial

To date, no biomarkers for second-line anti-angiogenic treatment in RAS wild type (wt) metastatic colorectal cancer (mCRC) patients (pts) with progression after first-line anti-epidermal growth factor receptor (EGFR) agents have been validated. Data on dynamic change of circulating pro-angiogenic factors levels during treatment from the pre-planned interim analysis of DISTINCTIVE trial (NCT04252456) are presented.

Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era.

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

A retrospective analysis of real-world time on treatment and overall survival in patients with metastatic colorectal cancer receiving cetuximab in third line.

e15575 Background: Colorectal cancer (CRC) is the 3rd leading cause of cancer-related deaths in the US. Anti-epidermal growth factor receptor agents improve outcomes of patients with metastatic CRC (mCRC) and are used in multiple lines of therapy. However, real-world time on treatment (TOT) and overall survival (OS) of cetuximab in third-line (3L) have not been described. Therefore, we sought to evaluate TOT, OS, and associated factors in a retrospective study. Methods: A total of 617 patients diagnosed with mCRC and received 3L treatment with cetuximab containing regimens regardless of prior therapies were selected from the nationwide Flatiron electronic health record database (January 2013 - August 2020). TOT was defined as the time from initiation of cetuximab in 3L (index date), to the last recorded date of cetuximab administration. End of therapy was defined if the patients progressed to subsequent line of therapy, or had a record of death. OS was calculated from the index date to date of death or censored to last visit date available. The Kaplan-Meier estimates, and stepwise Cox models were adapted to identify and calculate hazard ratios (HR), and 95% confidence intervals (CI) for factors associated with TOT and OS. Results: Majority of patients receiving 3L treatment with cetuximab containing regimens were: treated in the community setting (96%), less than 65 years old (58%), overweight with a median body mass index (BMI) of 26.2 kg/m² and, received FOLFOX regimens in 1L (46%) and FOLFIRI in 2L (47%). The most common cetuximab containing regimens were cetuximab+irinotecan (36%) and cetuximab+FOLFIRI (34%) and cetuximab monotherapy. The median TOT (mTOT) for patients receiving 3L cetuximab containing regimens was 3.48 months (median interquartile range (mIQR) 3.02-4.17). Higher BMI (obese vs. underweight HR = 0.44, 95% CI 0.28-0.68) was associated with a longer mTOT, while having an ECOG score ≥1 was associated with a shorter mTOT (vs. ECOG = 0, HR = 1.37, 95% CI 1.10-1.72). Also, of all cetuximab containing regimens in 3L cetuximab + FOLFIRI (vs. cetuximab monotherapy) was associated with a longer mTOT (4.63 months, mIQR 3.45-5.55). The median OS (mOS) for patients receiving 3L cetuximab containing regimens was 11.99 months (mIQR 10.87-12.94). Similarly, higher BMI (obese vs. underweight HR = 0.25, 95% CI 0.16-0.40) and 3L cetuximab + FOLFIRI (mOS= 14.3 months, mIQR 11.66-16.85) vs. cetuximab monotherapy were associated with a longer mOS. OS did not differ by patient’s geographic region (South vs Midwest, p-value 0.35). Conclusions: In this real-world retrospective analysis cetuximab + irinotecan and cetuximab + FOLFIRI were the most common 3L cetuximab regimens. The most common treatment regimens in 1L and 2L were FOLFOX and FOLFIRI respectively. Overall, BMI and treatment regimens received in 3L were associated with mTOT and mOS.

Real-world time on treatment and overall survival in patients with metastatic colorectal cancer receiving cetuximab in second line after failing irinotecan or oxaliplatin-based regimens.

e15568 Background: Anti-epidermal growth factor receptor agents are increasingly used in later lines of therapy for the treatment of metastatic colorectal cancer (mCRC). However, the real-world time on treatment (TOT) and overall survival (OS) of patients with mCRC receiving cetuximab in second-line (2L) setting have not been described. Therefore, we sought to evaluate TOT, OS and identify factors associated with longer TOT and OS based on retrospective observational data. Methods: A total of 1,011 patients were selected from the nationwide Flatiron electronic health record database (January 2013-August 2020) who were: 1) diagnosed with mCRC, 2) received 2L treatment with cetuximab containing regimens, and 3) had failed oxaliplatin/irinotecan-based regimens in first-line (1L). TOT was defined as the time from initiation of cetuximab in 2L (index date), to the last date showing evidence of cetuximab administration. End of therapy was defined if patients progressed to third-line of therapy, or having a death record. OS was calculated from the index date to the date of death or censored to last visit date available. The Kaplan-Meier estimates, and stepwise Cox models were adapted to calculate hazard ratios (HR) and 95% confidence intervals (CI) for associated factors. Results: Majority of patients receiving 2L treatment with cetuximab containing regimens were: less than 65 years old (58%), male (60%), had a median body mass index (BMI) of 26.6 kg/m², received FOLFOX regimens in 1L (61%) and were treated in the community setting (96%). The most common 2L regimens were cetuximab+FOLFIRI (46%) and cetuximab+Irinotecan (29%). Overall, the median TOT (mTOT) for patients receiving 2L cetuximab was 3.94 months (median Interquartile range (mIQR) 3.51-4.40), and median OS (mOS) was 14.36 months (mIQR 13.01-15.70). Of all cetuximab containing regimens, receiving cetuximab+FOLFIRI in 2L (mTOT = 4.43 months, mIQR 3.71-5.36), KRAS wild-type (vs. KRAS+), and receiving 2L cetuximab after prior therapy with 1L CapeOX (vs. FOLFOX) were associated with a longer mTOT. Living in the South region (vs. Midwest) was associated with a shorter mTOT. Having a higher BMI (obese vs. underweight HR = 0.46, 95% CI 0.32-0.66) was associated with a longer mOS, while receiving cetuximab+FOLFOX in 2L (mOS = 10.97 months, mIQR 5.55-14.06) or being older (≥65 vs. &lt; 65 years; HR = 1.24, 95% CI 1.05-1.46) were associated with a shorter mOS. Conclusions: In this real-world retrospective analysis we show TOT and OS overall in mCRC patients who received cetuximab containing regimens in 2L. These patients were mostly male, &lt; 65 years, and majority received FOLFOX regimens in 1L therapy. Key factors associated with TOT and OS were treatment regimens received in 1L and 2L. In addition, KRAS status and region were associated with TOT, while BMI and age were associated with OS only.

Efficacy and safety of anti-epidermal growth factor receptor agents for the treatment of oesophageal cancer: a systematic review and meta-analysis

ObjectivesDespite remarkable advances in the treatment of oesophageal cancer (OC), the role of antiepidermal growth factor receptor (anti-EGFR) agents in treating OC remains controversial. Herein, a systematic review and meta-analysis...

Metastatic Colorectal Cancer. First Line Therapy for Unresectable Disease.

Colorectal cancer (CRC) is a commonly diagnosed malignancy. The prognosis of patients with unresectable, metastatic colorectal cancer (mCRC) is dismal and medical treatment is mainly palliative in nature. Although chemotherapy remains the backbone of treatment, the landscape is changing with the understanding of its heterogeneity and molecular biology. First-line therapy relies on a combination of chemotherapy and targeted therapies, according to clinical patient characteristics and tumor molecular profile. Here we review current evidence from randomized clinical trials for using chemotherapy doublets or triplets, and for the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents. Novel therapies developed for small, selected populations are also discussed.

Patient preferences and predicted relative uptake for targeted therapies in metastatic colorectal cancer: a discrete choice experiment

Objective Ras wild-type metastatic colorectal cancers (mCRC) may be treated with anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor (EGFR) agents. We aim to estimate patients’ preferences for mCRC treatment and relative importance of cost, efficacy improvement, avoidance of side effects and therapy convenience, and relative uptake between profiles that resemble Bevacizumab (anti-VEGF) and Cetuximab (anti-EGFR), two commonly prescribed mCRC targeted therapies. Methods Discrete choice experiment (DCE) was administered to English- or Chinese-speaking Stage 2 or 3 colon cancer patients at the National Cancer Centre Singapore. DCE attributes comprise progression-free survival (PFS), severity of acne-like skin rashes, severity of bleeding, out-of-pocket cost per month and frequency of drug administration. Mixed logit model was used to calculate preference weights for all attribute levels. Subgroup analyses were conducted by interacting attribute levels with selected respondent characteristics. Relative uptake rates for various medication scenarios were studied. Results 169 respondents aged 61.5 ± 10.5 years completed the survey. They placed the greatest weight on cost, followed by bleeding and skin rashes, then PFS and finally frequency of drug administration. This was similarly observed in the subgroup analyses. A scenario with shorter PFS but less severe side effects has a slightly higher relative uptake at 55%. One quarter of respondents reported that they would not take the treatment they preferred in the choice task. Conclusion Patients were willing to trade off some degree of efficacy to avoid certain severity of side effects. It is therefore crucial for patients and physicians to discuss patients’ preferences and circumstances to understand which attributes are more important, as well as patients’ views on the trade-offs between treatment benefits and risks.

Management of skin adverse reactions in oncology.

Chemo and targeted anticancer therapies present significant skin adverse reactions, which impair the patients' quality of life. Cutaneous toxicities lead to poor treatment adherence, drug cessation, and psychosocial distress. This review aims to summarize the current knowledge concerning the prevention and management of skin toxicity arising from these therapies. A systematic literature search on online databases was conducted. The categorization of the main preventive and treatment measures was performed according to the level of evidence. Management of skin adverse reactions of oncology treatments is very heterogeneous, which can be explained by the lack of sound evidence-based treatments. The most studied adverse effects are papulopustular eruption, xerosis, and hand-foot syndrome. Prevention of xerosis stands out as the strategy most supported by level II studies. With respect to treatment, the use of antibiotics in papulopustular eruption resulting from anti-epidermal growth factor receptor agents is the most evidence-based approach. In general, the number of studies published in the literature classified with a level II of evidence (52%) is similar to the ones classified as level IV (33%), making clear the need of more randomized controlled trials regarding the effectiveness of preventive and treatment measures of skin adverse reactions of chemo and targeted anticancer therapies.

Comparative Cost-utility Analysis of Regorafenib and Trifluridine/Tipiracil in The Treatment of Metastatic Colorectal Cancer in Japan

PurposeThis study evaluated the cost utility of regorafenib and trifluridine/tipiracil (T/T) compared with that of best supportive care (BSC) in the treatment of patients with metastatic colorectal cancer previously treated with, or not considered candidates for, available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies; anti–vascular endothelial growth factor agents; and anti–epidermal growth factor receptor agents, in Japan. MethodsEfficacy data, utility values, and costs were extracted from published studies. The cost and effectiveness of regorafenib and of T/T were compared with those of BSC and examined between the 2 agents over a 5-year time horizon using a partitioned survival analysis. The health outcomes were life-years (LYs) and quality-adjusted life-years (QALYs) gained. The costs were year-2018 revisions to the drug prices and medical fees. The uncertainty and robustness of the model were verified by 1-way sensitivity analysis, probability sensitivity analysis, and scenario analysis compared with different clinical studies. A 2% per-annum discount was applied to expenses and QALYs. The willingness-to-pay threshold used was 5 million Japanese yen (JPY). FindingsRegorafenib and T/T had incremental costs of 11,898,982 JPY (107,781 US dollars [USD]) and 5,000,141 JPY (45,291 USD), incremental effects of 0.249 QALYs (0.280 LYs) and 0.344 QALYs (0.421 LYs), and incremental cost-effectiveness ratios of 47,773,791 JPY (432,734 USD) and 14,550,577 JPY (131,799 USD) per QALY, respectively. Results of sensitivity analyses all exceeded the willingness-to-pay threshold of 15 million JPY. In the comparison of the 2 agents, T/T was a dominant alternative over regorafenib. ImplicationsAs a third-line or later treatment of metastatic colorectal cancer in Japan, T/T is cost-effective compared with BSC, whereas regorafenib is not. It is necessary to adjust the price of regorafenib based on the results of this analysis, with the improvement of clinical parameters such as survival time and adverse events.

BRAF and KRAS mutations in metastatic colorectal cancer: future perspectives for personalized therapy.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide and 30% of patients with CRC experience metastasis. Patients with metastatic colorectal cancer (mCRC) have a 5-year overall survival rate of <10%. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and V-Ki-ras2 Kirsten ratsarcoma viral oncogene homolog (KRAS) mutations are mostly studied in mCRC, as clinical trials found that first-line chemotherapy with anti-epidermal growth factor receptor agent confers limited efficacy for mCRC. Treatment decisions for early-stage mCRC do not consider BRAF or KRAS mutations, given the dramatically poor prognosis conferred by these mutations in clinical trials. Thus, it is necessary to identify patients with mCRC harboring BRAF or KRAS mutations to formulate rational therapeutic strategies to improve prognosis and survival. BRAF and KRAS mutations occur in ∼10% and ∼44% of patients with mCRC, respectively. Although the survival rate of patients with mCRC has improved in recent years, the response and prognosis of patients with the aforementioned mutations are still poor. There is a substantial unmet need for prospective personalized therapies for patients with BRAF- or KRAS-mutant mCRC. In this review, we focus on BRAF and KRAS mutations to understand the mechanisms underlying resistance and improving the response rate, outcomes, and prognosis of patients with mCRC bearing these mutations and to discuss prospective personalized therapies for BRAF- and KRAS-mutant mCRC.

Trifluridine/tipiracil: A practical guide to its use in the management of refractory metastatic colorectal cancer in Australia.

Trifluridine/tipiracil is available on the Australian Pharmaceutical Benefits Scheme for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-vascular endothelial growth factor agents and anti-epidermal growth factor receptor agents. This article reviews trifluridine/tipiracil clinical data and presents practical information on its use in the management of refractory mCRC in Australia. Whereas the primary mechanism of action of fluoropyrimidines such as fluorouracil (5-FU) and capecitabine is enzyme inhibition of nucleotide synthesis, trifluridine/tipiracil primarily acts by incorporation into DNA, resulting in DNA dysfunction. Trifluridine/tipiracil has activity in patients with 5-FU-resistant tumors and can be considered in patients with prior intolerance or toxicity to 5-FU. In the pivotal phase III RECOURSE trial evaluating trifluridine/tipiracil in chemotherapy-refractory mCRC, efficacy benefits were observed across all a priori prognostic subgroups including those defined by age (≥65 and ≥75 years), geographical origin, primary tumor site or KRAS status. Trifluridine/tipiracil therapy benefits appropriately selected patients who have an ECOG performance status of 0 or 1, with no more than mild hepatic impairment or mild-to-moderate renal impairment, and who are capable of adhering to oral therapy safely. Appropriate dosing, monitoring for adverse events and effective management of side effects are essential.