In patients with RAS wild-type metastatic colorectal cancer (mCRC), an anti-epidermal growth factor receptor (EGFR) monoclonal antibody plus chemotherapy is a standard option for treatment in the first-line setting. Patients who progress while on treatment with anti-EGFR-based therapy can be resistant to further anti-EGFR treatment, but evidence suggests that the anti-EGFR-resistant clones decay, thereby opening the potential for rechallenge or reintroduction in later lines of treatment. Results from recent clinical studies have shown that some patients with mCRC who are rechallenged with anti-EGFR monoclonal antibodies exhibit durable responses. While other therapies have demonstrated improved overall survival in chemorefractory mCRC over the past decade, rechallenge with anti-EGFR monoclonal antibodies in later lines of treatment represents a new option that deserves further investigation in clinical trials. In this review, we summarize the molecular rationale for rechallenge or reintroduction in patients with mCRC who have progressed on earlier-line anti-EGFR treatment and examine the current evidence for using liquid biopsy as a method for selecting rechallenge as a therapeutic option. We also provide an overview of published trials and trials in progress in this field, and outline the potential role of rechallenge in the current clinical setting.

Aim: To compare healthcare resource utilization (HRU) and healthcare costs (HC) for every-2-week (Q2W) versus weekly (Q1W) cetuximab in metastatic colorectal cancer (mCRC). Patients & methods: Patients with mCRC receiving cetuximab plus chemotherapy in a line-agnostic setting. Cohort study of patients with mCRC treated with cetuximab and chemotherapy in IBM MarketScan. Analyses were weighted by inverse probability of treatment based on propensity score. Results: HRU was numerically lower with the Q2W versus Q1W regimen (weighted mean, 8.1 vs 9.5 encounters per-patient-per-month). The weighted average of HC was $17,653 and $16,469 per-patient-per-month for the Q2W and Q1W regimens, respectively; the difference between regimens decreased when restricting to CRC-related claims. Conclusion: HRU was lower and HC were similar between the Q2W and Q1W regimens.

23 Background: Cetuximab (CET) administered weekly (q1w) at 250 mg/m², after an initial dose of 400 mg/m², is approved in combination with chemotherapy (CT) for the treatment of (K) RAS wild-type metastatic colorectal cancer (mCRC). The use of CET 500 mg/m2 administered with CT every 2 weeks (q2w) is according to US clinical practice guidelines and observed routinely. In this study, we compared q2w vs q1w regimens on overall survival (OS) in a presumed first-line (1L) treatment subcohort and present updated data on the noninferiority of q2w vs q1w in line-agnostic (1L+) treatment using US real-world data. Methods: Using IBM MarketScan, a large US insurance claims database, we classified a cohort of mCRC patients treated between 07/2010 and 12/2016 with CET+CT as q1w or q2w based on observed infusion patterns. Absence of mCRC-related treatment claims preceding CET initiation date (defined as the index date) qualified as CET treated in 1L. A validated algorithm was used to determine patient death. Confounding was accounted for using high-dimensional propensity scoring (hdPS) with inverse probability of treatment weights. OS was compared using Cox proportional hazards regression. Imbalanced confounders after hdPS were added to the Cox model. In 1L+, noninferiority of the q2w regimen was tested with a margin hazard ratio (HR) of 1.25. However, noninferiority could not be tested in 1L due to the small sample size; a test for difference was used instead. Results: Of 2,730 CET-exposed mCRC patients (updated), 1,779 (65.2%) and 951 (34.8%) were classified in q1w and q2w groups, respectively, among which 557 (31.3%) and 316 (33.2%) received CET in 1L. The HR (95% CI) for OS of q2w vs q1w in 1L was 1.10 (0.92-1.31; crude), and 1.05 (0.86-1.29; adjusted; p for difference: 0.625). In 1L+, crude and adjusted HRs were 1.05 (0.94-1.18) and 0.94 (0.85-1.03), respectively, rejecting the inferiority hypothesis at p < 0.001. Conclusions: Only a third of patients received CET in 1L in this study. OS was statistically noninferior in q2w vs q1w in 1L+, and adjusted results in 1L suggest no differences between both treatment schedules. However, more data would be needed to formally test the noninferiority hypothesis in 1L.

Aim: To test the noninferiority of cetuximab administered every 2 weeks (Q2W) versus once weekly (Q1W) in treating metastatic colorectal cancer (mCRC) with regard to overall survival (OS). Patients: Patients receiving cetuximab plus chemotherapy for mCRC in a line-agnostic setting. Methods: This cohort study in IBM MarketScan followed patients from initiation of cetuximab for mCRC until the end of the data availability period, proxy-based death or loss of insurance coverage for >30 days. Results: The hazard ratio for OS was 0.94 (0.85-1.03), and the inferiority hypothesis was rejected at p < 0.001. No significant differences were noted in rates of safety events between Q2W and Q1W. Conclusion: Our real-world study confirmed the noninferiority of cetuximab administered Q2W versus Q1W for OS.

22 Background: Cetuximab (CET) 250 mg/m2 weekly (q1w) after an initial dose of 400 mg/m2 added to chemotherapy (CT) is licensed for treatment of (K)RAS wild-type metastatic colorectal cancer (mCRC). In practice, administration of CET 500 mg/m2 plus CT every 2 weeks (q2w) is common. We compared healthcare costs between q2w and q1w regimens in a US claims database study. Methods: A cohort of 2,943 mCRC patients CET-treated between 2010 and 2016, identified in IBM MarketScan, was analyzed for costs associated with CET+CT q2w vs q1w. All-category costs (ACC), stratified by overall outpatient (OO), inpatient (OI), and pharmacy (OP) claimed costs during the exposure period, were compared between groups. Additionally, subcategories of CRC- and skin toxicity (ST)–related claims were explored, and imputation of capitated claim costs was performed. Patients were weighted by the stabilized inverse probability of treatment (IPTW) based on a high-dimensional propensity score to control for confounding. Generalized linear models (GLMs) with gamma distributions were used to compare regimens. Inflation-adjusted costs (2016 US dollars) are presented per patient per month ($PPPM) with 95% CIs. Results: 1,779 and 951 patients were classified as q1w and q2w, respectively. Median ACC were 14,089 (q2w) vs 14,034 (q1w) $PPPM. Mean ACC and OO, OI, and OP costs are summarized in the table. CIs overlapped in each category, with GLMs showing no statistically significant differences. This finding was similar for CRC and ST subcategories. Conclusions: No cost differences were found between q2w and q1w regimens. In line with published noninferiority of overall survival with the q2w regimen, it represents an effective, cost-neutral option for treating mCRC patients. [Table: see text]

Cetuximab and panitumumab are two distinct monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR), and both are widely used in combination with chemotherapy or as monotherapy to treat patients with RAS wild-type metastatic colorectal cancer. Although often considered interchangeable, the two antibodies have different molecular structures and can behave differently in clinically relevant ways. More specifically, as an immunoglobulin (Ig) G1 isotype mAb, cetuximab can elicit immune functions such as antibody-dependent cell-mediated cytotoxicity involving natural killer cells, T cell recruitment to the tumor, and T cell priming via dendritic cell maturation. Panitumumab, an IgG2 isotype mAb, does not possess these immune functions. Furthermore, the two antibodies have different binding sites on the EGFR, as evidenced by mutations on the extracellular domain that can confer resistance to one of the two therapeutics or to both. We consider a comparison of the properties of these two antibodies to represent a gap in the literature. We therefore compiled a detailed, evidence-based educational review of the known molecular, clinical, and functional differences between the two antibodies and concluded that they are distinct therapeutic agents that should be considered individually during treatment planning. Available data for one agent can only partly be extrapolated to the other. Looking to the future, the known immune activity of cetuximab may provide a rationale for this antibody as a combination partner with investigational chemotherapy plus immunotherapy regimens for colorectal cancer.

e15087 Background: After an initial dose of 400 mg/m², cetuximab (CET) at a dose of 250 mg/m² in combination with chemotherapy (CT) is approved for once-weekly (q1w) use in the treatment of RAS wild-type metastatic colorectal cancer (mCRC). However, off-label use of CET 500 mg/m2 administered every other week (q2w) has been observed in clinical practice. This study aimed to test the noninferiority of q2w vs q1w administration on overall survival (OS) using US claims data. Methods: Using IBM MarketScan, a large US insurance claims database, a cohort of patients with mCRC treated with CET + CT between 2010 and 2016 was identified and classified as q1w or q2w based on observed infusion patterns. The initial CET prescription was defined as the index date, and patient death was determined using a previously published algorithm. Confounding was accounted for using high-dimensional propensity scoring (hdPS) methodology with inverse probability of treatment weighting (IPTW). OS for both groups was compared using Cox proportional hazards regression. Confounders that remained imbalanced after hdPS with IPTW were added to the Cox model. The noninferiority of the q2w regimen was tested with a margin hazard ratio (HR) of 1.25 for q2w vs q1w. Results: 2,869 patients with mCRC exposed to CET were identified of which 1,865 (65.0%) and 1,004 (35.0%) were classified in the q1w and q2w groups, respectively. The mean age of patients was 60.1±11.7 years for q1w and 58.1±11.1 years for q2w. Most patients were male: 57.5% and 60.8% in q1w and q2w, respectively. Approximately 70% of patients in both groups had received prior treatment for mCRC. The most frequently used CT with CET was irinotecan based (64.5% in q1w and 76.5% in q2w). There were 1,628 deaths observed during follow-up (56.7%). After hdPS with IPTW adjustment, differences remained in associated CT (standardized difference <0.25). Crude HR for OS was 1.05 (95% CI, 0.94-1.18), and adjusted HR for OS was 1.04 (95% CI, 0.93-1.17). The inferiority hypothesis was rejected at p<0.001. Conclusions: In this large US claims database, when assessing OS, the q2w administration schedule was found to be noninferior to the q1w schedule in patients with mCRC.

The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with chemotherapy is a standard of care in the first-line treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC) and has demonstrated efficacy in later lines. Progressive disease (PD) occurs when tumours develop resistance to a therapy, although controversy remains about whether PD on a combination of chemotherapy and targeted agents implies resistance to both components. Here, we propose that some patients may gain additional clinical benefit from the reuse of cetuximab after having PD on regimens including cetuximab in an earlier treatment line. We conducted a non-systematic literature search in PubMed and reviewed published and ongoing clinical trials, focusing on laterline cetuximab reuse in patients with mCRC. Evidence from multiple studies suggests that cetuximab can be an efficacious and tolerable treatment when continued or when fit patients with mCRC are retreated with it after a break from anti-EGFR therapy. Furthermore, on the basis of available preclinical and clinical evidence, we propose that longitudinal monitoring of RAS status may identify patients suitable for such a strategy. Patients who experience progression on cetuximab plus chemotherapy but have maintained RAS wt tumour status may benefit from continuation of cetuximab with a chemotherapy backbone switch because they have probably developed resistance to the chemotherapeutic agents rather than the biologic component of the regimen. Conversely, patients whose disease progresses on cetuximab-based therapy due to drug-selected clonal expansion of RAS-mutant tumour cells may regain sensitivity to cetuximab following a defined break from anti-EGFR therapy. Looking to the future, we propose that RAS status determination at disease progression by liquid, needle or excisional biopsy may identify patients eligible for cetuximab continuation and rechallenge. With this approach, treatment benefit can be extended, adding to established continuum-of-care strategies in patients with mCRC.

An accurate blood‐based RAS mutation assay to determine eligibility of metastatic colorectal cancer (mCRC) patients for anti‐EGFR therapy would benefit clinical practice by better informing decisions to administer treatment independent of tissue availability. The objective of this study was to determine the level of concordance between plasma and tissue RAS mutation status in patients with mCRC to gauge whether blood‐based RAS mutation testing is a viable alternative to standard‐of‐care RAS tumor testing. RAS testing was performed on plasma samples from newly diagnosed metastatic patients, or from recurrent mCRC patients using the highly sensitive digital PCR technology, BEAMing (beads, emulsions, amplification, and magnetics), and compared with DNA sequencing data of respective FFPE (formalin‐fixed paraffin‐embedded) tumor samples. Discordant tissue RAS results were re‐examined by BEAMing, if possible. The prevalence of RAS mutations detected in plasma (51%) vs. tumor (53%) was similar, in accord with the known prevalence of RAS mutations observed in mCRC patient populations. The positive agreement between plasma and tumor RAS results was 90.4% (47/52), the negative agreement was 93.5% (43/46), and the overall agreement (concordance) was 91.8% (90/98). The high concordance of plasma and tissue results demonstrates that blood‐based RAS mutation testing is a viable alternative to tissue‐based RAS testing.

Background Inhibition of the epidermal growth factor receptor (EGFR) extends patient survival in multiple tumor types. Skin toxicities are the most common adverse event (AE) elicited by EGFR inhibitors. Here, we provide deeper insights into patients’ and physicians’ acceptance of the risk/benefit trade-offs of skin toxicities during cancer therapy, including comparison of their perceptions and experiences with dermatologic AEs. Methods A multinational survey of 195 patients and 120 physicians was conducted to gauge attitudes regarding skin toxicities as an AE during cancer therapy. Results Skin toxicities were identified by patients and physicians as the AE that is most discouraging to patients when undergoing cancer therapies. Skin toxicities were cited as causing pain, impairing quality of life, and proving difficult to manage. Despite these negative influences, the majority of patients (71%) indicated they were willing to accept skin toxicities as an AE of an effective therapy. Indeed, the majority of patients and physicians preferred a more effective therapy that induces more severe skin toxicities than a less efficacious therapy that induces less severe skin toxicities; interestingly, patients were willing to accept a higher likelihood of severe skin toxicities than physicians. Conclusion In this examination of patients’ perspectives, we found that patients were willing to accept skin toxicities if they were the anticipated byproduct of a more effective therapeutic regimen. Important differences were observed between patients’ and physicians’ attitudes regarding risk/benefit trade-offs during cancer therapy, suggesting that patient’s considerations and shared decision-making are key to cancer care.