Clinical and Translational Oncology (2022) 24:2155–2165 https://doi.org/10.1007/s12094-022-02868-x RESEARCH ARTICLE Randomized phase II trial of FOLFIRI‑panitumumab compared with FOLFIRI alone in patients with RAS wild‑type circulating tumor DNA metastatic colorectal cancer beyond progression to first‑line FOLFOX‑panitumumab: the BEYOND study (GEMCAD 17‑01) Jorge Aparicio1 · Anna C. Virgili Manrique2 · Jaume Capdevila3,4 · Félix Muñoz Boza5 · Patricia Galván6 · Paula Richart1 · Helena Oliveres6 · David Páez2 · Jorge Hernando3 · Sara Serrano5 · Ruth Vera7 · Xavier Hernandez‑Yagüe8 · Rafael Álvarez Gallego9 · M. Carmen Riesco‑Martinez10 · Xavier García de Albeniz11 · Joan Maurel6 Received: 11 April 2022 / Accepted: 27 May 2022 / Published online: 27 June 2022 © The Author(s) 2022 Abstract Purpose Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB). Methods In this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38). Results Between February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B. Conclusions The BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in meta- static colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation. Keywords Colorectal cancer · Metastatic disease · Second line therapy · Panitumumab · Liquid biopsy Introduction 30 months. So far, only a few therapeutic agents have shown efficacy in metastatic disease: fluoropyrimidines, oxalipl- Colorectal cancer (CRC) represents 12.7% of all new atin, irinotecan, anti-epidermal growth factor receptor (anti- tumors in the European Union (EU) population [1]. Up to EGFR) drugs as cetuximab and panitumumab, and anti- 50% of patients will develop metastases during their evolu- angiogenic drugs. For fit patients, they are frequently used tion. For those with unresectable metastatic disease, treat- upfront in combination, i.e., a chemotherapy regimen plus a ment is mainly palliative and median survival time is about targeted agent (according to their molecular profile) [2–4]. After progression, second-line regimens include chemo- therapy crossover with or without targeted agents. However, * Jorge Aparicio treatment options in this setting have limited benefit, and japariciou@seom.org thus, further clinical investigation is warranted. * Joan Maurel Activating mutations in KRAS and NRAS are predic- jmaurel@clinic.cat tive biomarkers of resistance to anti-EGFR monoclonal Extended author information available on the last page of the article 13 Vol.:(0123456789) 2156 Clinical and Translational Oncology (2022) 24:2155–2165 antibodies in metastatic CRC. In addition, mutations occur- ECOG performance status of 0–2, and adequate bone mar- ring in BRAF, PIK3CA, and PTEN genes have been associ- row, liver and renal function. Patients should have been pre- ated with resistance to these drugs. Panitumumab is labeled viously treated in first line with P-FOLFOX, should have in EU in combination with FOLFOX (fluorouracil, folinic achieved complete response (CR), partial response (PR), or acid, and oxaliplatin) in first line (P-FOLFOX) [5] and with stable disease (SD), and have ctDNA WT RAS status deter- FOLFIRI (fluorouracil, folinic acid, and irinotecan) in sec- mined before randomization. The main exclusion criteria ond line (P-FOLFIRI) [6] for RAS wild-type (WT) patients. were relevant cardiovascular disease, central nervous system The clinical value of anti-EGFR rechallenge strategy (i.e., metastases, unresolved toxicities of previous systemic treat- re-treat with the anti-EGFR in patients previously treated ment, acute or subacute intestinal occlusion, active inflam- with anti-EGFR and with progressive disease to a second matory bowel disease, and major surgery or radiotherapy line) has not been definitively demonstrated in randomized within 28 days prior to inclusion in the study. The trial was clinical trials, although some evidence suggests that it approved by the Ethics Committees at each participating could have potential value [7–10]. In a somewhat different institution and was carried out in accordance with the Dec- approach, Ciardello et al. tested for the first time cetuxi- laration of Helsinki. All patients provided written informed mab continuation plus chemotherapy crossover beyond first consent. progression and showed its potential therapeutic efficacy in molecularly selected patients (KRAS, NRAS, BRAF, and Randomization and treatment PIK3CA WT status, assessed in baseline tumor biopsy by next-generation sequencing) [7]. LB for ctDNA analysis was collected at study entry and at Plasma circulating tumor DNA (ctDNA) determination disease progression with Idyilla technology. After confirmed of RAS and BRAF has been shown to correlate well with progression to first- line P-FOLFOX and having verified the tissue determination in multiple studies with different tech- absence of mutations in ctDNA, patients were centrally ran- niques [11–14]. Therefore, continuous monitoring of RAS domized in a 3:2 ratio to P-FOLFIRI (arm A) or FOLFIRI status is useful during the course of the disease, because it alone (arm B). Random assignment was stratified by primary avoids the inconveniences of repeating tumor tissue samples tumor sidedness (left vs. right) and, after an amendment biopsies and is more representative of the current mutational dated January 20, 2020, by time since last panitumumab status of the disease. Prospective and retrospective cohort administration (≤ 3 months vs. > 3 months). studies suggest that ctDNA RAS mutations detected by liq- On day 1 of each 14-day period, patients in the FOLFIRI uid biopsy (LB) can identify metastatic colorectal cancer group received an infusion of 200 mg l-folinic acid over patients with intrinsic or acquired anti-EGFR resistance 1.5–2 h(s), 180 mg per square meter of irinotecan over 1.5 h, [15–17]. Recently, Cremolini et al. suggested in a retro- 400 mg per square meter bolus of 5-fluorouracil (5-FU) and spective analysis of a prospective phase II clinical trial [18] then 46-h continuous infusion (CI) of 2400 mg per square that a rechallenge strategy with cetuximab benefits specially meter of 5-fluorouracil; patients in the P-FOLFIRI group patients who maintain RAS and BRAF WT status in LB. received an infusion of panitumumab 6 mg per kilogram We aimed to explore the clinical activity of maintaining over 60 min before FOLFIRI. Those patients ≥ 70 years old panitumumab in combination with FOLFIRI beyond pro- could start FOLFIRI with a 20% dose reduction. Treatment gression to first-line P-FOLFOX in patients with no RAS was continued until disease progression, unacceptable toxic mutations detected before second-line treatment by LB effects, or withdrawal of consent occurred. technology. Computed tomography imaging was performed at base- line and every 8 weeks until disease progression. Tumor response was evaluated according to Response Evaluation Methods Criteria in Solid Tumors (RECIST, version 1.1). Adverse events [assessed according to the National Cancer Institute- Study design and patients Common Toxicity Criteria for adverse events (AEs), version 4.03] were recorded continuously. BEYOND trial (GEMCAD 17-01) is an academic, open- label, randomized phase II trial performed at 15 Spanish Statistical analysis hospitals. This trial is registered with EudraCT, no.: 2017- 004519-3 8. We enrolled patients aged 18 years or older The primary endpoint was 6-month progression-free sur- with histologically confirmed adenocarcinoma of colon vival (PFS), defined as the proportion of subjects still alive or rectum, measurable metastatic disease not amenable to and progression free at 6 months, and analyzed by intention surgical resection, confirmed disease progression to first- to treat. The aim of the control arm was to test the validity of line treatment according to RECIST criteria (version 1.1), the assumption of null effect (6-month PFS of 30%). Sample 13 Clinical and Translational Oncology (2022) 24:2155–2165 2157 size was determined through a Simon's two-stage model not meeting inclusion/exclusion criteria: sixteen patients assuming a null effect corresponding to a 6-month PFS of because of RAS mutations (32.6%), one patient because 30% and a treatment effect corresponding to a 6-month PFS not having achieved at least stable disease to first-line of 50%, with an alpha error of 0.05, and a beta error of P-FOLFOX and one patient due to CNS metastasis at 0.2. The sample needed for this study was 46 evaluable sub- screening. Of 31 eligible patients, 18 were randomized jects in arm A. Considering 10% of possible losses, the final to arm A and 13 to arm B (Fig. 1). Interim analysis was patient number projected to be included was 51 in arm A conducted as planned, showing 6 patients without progres- and 34 in arm B. Under this design, an interim analysis was sion 6 months after the inclusion of 15 patients in arm A; planned 6 months after the inclusion of the first 15 subjects therefore, the study continued. However, it was prema- in arm A and, if the number of patients without progression turely closed due to low recruitment. at 6 months in arm A was less than or equal to 5, the trial Baseline characteristics were well balanced across study would be stopped prematurely because of futility. Analysis arms (Table 1). There were no major differences in time of PFS at 6 months was based on the Kaplan–Meier esti- from the last dose of first-line chemotherapy, time from mator. The survival function as well as the median [95% first-line panitumumab to randomization or in the duration confidence interval -95% CI-] time to event were estimated of panitumumab in previous line. Median relative dose by means of the Kaplan–Meier method. Group compari- intensity for irinotecan, bolus 5-FU, and CI 5-FU was sim- sons were done using the (stratified) log-rank test and the ilar in both arms. Median treatment duration and median (stratified) hazard ratios (95% CI) were estimated with the number of subjects with dose reductions and dose inter- Cox model. Secondary analyses were overall response rate ruptions were higher in arm A. Median number of cycles (ORR), overall survival (OS), safety and tolerability, as well administered was 12 (Interquartile Range, IQR 7–17) as biomarker analysis by tissue and LB. for arm A and 6 (IQR 5–9) for arm B. The only imbal- ances corresponded to performance status (ECOG PS), with more patients in arm B having ECOG PS 1 (76.9% Results vs 44.4% in Arm A) and more than one organ affected (100% vs. 55.6%). Altogether, most patients were male, Patients 42% had an ECOG PS of 0, left colon was the primary tumor site in 77.4%, and metastases were located mainly in From February 2019 through November 2020, 49 patients the liver and lungs. The median duration of follow-up was were screened for RAS/BRAF/PI3K mutations in ctDNA 9.5 months (IQR 6.0–13.0) with P-FOLFIRI and 7 months prior to enrollment. Eighteen patients were excluded by (IQR, 5.0–9.0) with FOLFIRI. Fig. 1  Study flowchart Between Feb, 2019 and Nov, 2020 Assessed for eligibility (N=49) Excluded (N=18) ctDNA RAS mutation (N=16) Other Inclusion/Exclusion criteria (N=2) Randomized: 31 patients Allocated to FOLFIRI + Allocated to FOLFIRI (N=13) Panitumumab (N=18) 13 2158 Clinical and Translational Oncology (2022) 24:2155–2165 Table 1  Baseline patients and Group A (N = 18) Group B (N = 13) Total (N = 31) disease characteristics Age (years) Median [Q1–Q3] 59 [51–66] 67 [62–74] 62 [55–73] Min–Max 31–78 55–84 31–84 Gender Female n (%) 8 (44.4) 3 (23.1) 11 (35.5) Male n (%) 10 (55.6) 10 (76.9) 20 (64.5) Primary tumor location Left side n (%) 13 (72.2) 11 (84.6) 24 (77.4) Right side n (%) 5 (27.8) 2 (15.4) 7 (22.6) ECOG ECOG 0 n (%) 10 (55.6) 3 (23.1) 13 (41.9) ECOG 1 n (%) 8 (44.4) 10 (76.9) 18 (58.1) CEA (ng/ml) Median 11.0 [1.5–881.0] 20.6 [2.9–171.0] 16.6 [1.5–881.0] LDH (uKat/L) Median 5.55 [3.7, 8.5] 5.99 [2.9, 7.6] 5.61[3.5, 8.2] Metastases Liver metastases n (%) 14 (77.8) 10 (76.9) 24 (77.4) Lymph-node metastases n (%) 5 (27.8) 9 (69.2) 14 (45.2) Lung metastases n (%) 9 (50.0) 7 (53.8) 16 (51.6) Peritoneum metastases n (%) 4 (22.2) 4 (30.8) 8 (25.8) Other metastases n (%) 2 (11.1) 1 (7.7) 3 (9.7) Number of organs affected 1 n (%) 8 (44.4) 0 (0.0) 8 (25.8) 2 n (%) 5 (27.8) 8 (61.5) 13 (41.9) 3 or more n (%) 5 (27.8) 5 (38.5) 10 (32.3) Time from last dose of panitumumab to randomization (months) Mean (range) 2.67 (1.0–7.0) 2.15 (1.0–6.0) 2.45 (1.0–7.0) Time from last dose of first-line chemotherapy to randomization (months) Mean (range) 4.61 (1.0–18.0) 2.38 (1.0–6.0) 3.68 (1.0–18.0) Duration of panitumumab in first line Less than 3 months n (%) 0 (0.0) 2 (15.4) 2 (6.5) 3 months or more n (%) 18 (100) 11 (84.6) 29 (93.5) Efficacy (95% CI 10–20) and 10 months (CI 95% 3–15) in arms A and B, respectively, corresponding to a HR of 0.55 (95% One patient in each arm was not evaluable for response. CI 0.2–1.48) (Fig. 3B). At disease progression, mutational Confirmed partial tumor responses occurred in 6 patients status by LB was determined in 21 out of 24 patients, and (33%; 95% confidence interval CI 13–59) in arm A and in emergent mutations in RAS were found in 4 out 11 patients 1 patient (7.7%; 95% CI 0.2–36) in arm B. Disease stabili- (36%) in arm A and in 2 out of 10 patients (20%) in arm B zations were seen in 9 (50%) and 7 (54%) patients, respec- (Table 2). There was a BRAF mutational status change from tively, for a disease control rate of 83% in arm A and 62% mutated to wild type in arm B. in arm B. No complete responses were observed. Best over- all response and time of objective response are depicted Adverse events in Fig. 2. Six-month PFS was 66.7% (95% CI 40.9–86.6) in arm A and 38.5% (95% CI 13.8–68.4) in arm B, corre- All patients in the safety population presented at least one sponding to a hazard ratio (HR) of 0.42, (95% CI 0.14–1.23) adverse event. Overall incidence of grade 3 or 4 adverse (Fig. 3A). The median PFS was 11 months (95% CI 4–14) events was 66.7% in the P-FOLFIRI group and 53.9% in for arm A and 4 months (95% CI 2–8) for arm B (HR 0.58, the FOLFIRI group. The administration of P-FOLFIRI, 95% CI 0.25–1.3). Median overall survival was 13 months as compared with FOLFIRI alone, was associated with 13 Clinical and Translational Oncology (2022) 24:2155–2165 2159 Fig. 2  Radiologic response. A Waterfall plot of tumor response in evaluable patients, by treat- ment group. The bars show the best percentage change in the target lesions from baseline. The dashed horizontal lines at 20% and − 30% represent the progressive disease and partial response, respectively. *Patients with progression disease (PD) as best overall response due to new target lesions. B Swimmer plot showing time of objective response (PR or CR) and treat- ment duration more asthenia (50% vs. 38.5%), hypomagnesemia (38.9% P-FOLFIRI compared with 23.1% of patients treated vs. 7.7%), and acneiform rash (38.9% vs. 0.0%), all of with FOLFIRI. There were two AEs leading to death in them mainly grade 1–2. With P-FOLFIRI, there was a both treatment arms (one case in each arm); however, higher incidence of grade 3 diarrhea (16.7% vs. 7.7%), they were not judged as treatment-related by the study and in the FOLFIRI arm, there was more frequency of investigators. grade 3–4 anemia (15.4% vs 5.6%) (Table 3). Serious AEs were experienced by 44.4% of patients who received 13 2160 Clinical and Translational Oncology (2022) 24:2155–2165 Fig. 3  Survival curves. Kaplan– Meier curve for progression- free survival (A). Kaplan–Meier curve for overall survival (B) Discussion combination with anti-angiogenic drugs (bevacizumab, aflibercept, or ramucirumab). It suggests that anti-angi- In the continuum of care of metastatic CRC patients treated ogenic therapy beyond first progression can be effective in first line with chemotherapy plus the anti-vascular [21–24]. For RAS WT patients, anti-EGFR therapy (either endothelial growth factor bevacizumab, it has been shown alone or in combination with chemotherapy) is considered that a therapeutic option is second-line chemotherapy in standard in only a single line of therapy (i.e., first, second, 13 Clinical and Translational Oncology (2022) 24:2155–2165 2161 Table 2  Type of ctRAS mutation at progression Patient ctKRAS results Type of mutation ctNRAS results Type of mutation #P1 Mutation detected in KRAS CODON 61 Q61H No mutation #P2 Mutation detected in KRAS CODON 61 Q61H No mutation #P3 Mutation detected in KRAS CODON 12 G12D No mutation #P4 Mutation detected in KRAS CODON 12 G12C No mutation #P5 Mutation detected in KRAS CODON 61 Q61H Mutation detected in NRAS Q61R/K CODON 61 #P6 Mutation detected in KRAS CODON 61 Q61H No mutation or third) for non-pre-treated patients. More recently, in the differences are unlikely to arise from a worse outcome in setting of anti-EGFR therapy after a first-line anti-EGFR- the control arm. We decided to use FOLFIRI alone, instead containing regimen, two different experimental approaches of FOLFIRI plus bevacizumab in the control arm, because have been explored: (1) the rechallenge, i.e., reintroduction there is no clinical evidence that bevacizumab provides of anti-EGFR therapy after a second-line, anti-EGFR-free benefit compared to FOLFIRI based on phase III clinical schedule; and (2) the continuation of anti-EGFR therapy trials after first-line P-FOLFOX. Recently, a prospective (plus chemotherapy crossover) beyond progression to an clinical trial comparing second-line FOLFIRI plus cetuxi- upfront regimen. Both approaches have been assessed with mab vs FOLFIRI plus bevacizumab in RAS WT (based promising results in phase II trials [7, 18, 26]. The underly- on baseline tumor tissue determination) metastatic CRC ing hypothesis is that a sustained inhibition of EGFR signal- patients previously treated with FOLFOX plus cetuximab ing would continuously eliminate sensitive clones of RAS did not demonstrate cetuximab benefit in response rate WT tumor. Pending phase III confirmation, all these stud- or PFS [25], but suggested that only patients that retain ies suggested that the evaluation of RAS mutational status RAS WT status before second-line therapy would benefit on ctDNA might be helpful in selecting candidate patients. from rechallenge strategy [18]. Our ORR (33%; 95% CI Only patients with RAS and BRAF WT status at relapse 13–59%) and PFS (11 months; 95% CI 4–14 months) in determined by LB seem to benefit from these second- or the experimental arm are in line with that obtained with third-line therapies [15]. second-line P-FOLFIRI in FOLFOX only pre-treated The BEYOND trial shows a potential benefit of adding patients [6]. Recently, the CHRONOS study [26] with a panitumumab to FOLFIRI, in comparison with FOLFIRI rechallenge strategy showed similar ORR (30%, 95% CI alone, as second-line treatment for patients with ctDNA 12–47%) than that achieved with panitumumab monother- WT RAS status. Unfortunately, the estimates are imprecise apy in previously untreated patients [27]. because of the low number of patients recruited. This is a Despite initial benefit in the P-FOLFIRI arm, most novel approach evaluating the effects of continuing EGFR patients included in the study progressed. Interestingly, at inhibition for metastatic CRC beyond tumor progression to the time of disease progression, only 36% of patients in the a first-line panitumumab-containing treatment. Although P-FOLFIRI group showed emergent RAS mutations in LB, the calculated sample size of the study was not met, our which is in the range of other studies [28]. We have observed results do not rule out a beneficial effect of this re-treatment RAS emergent mutations in 20% of patients of the FOLFIRI strategy. Our final figures suggest that we would need 140 control arm, suggesting that acquisition of RAS mutations patients to be included in a phase III clinical trial to perform could appear also on holding anti-EGFR periods. All these a positive study. data confirm that alternative driven mutations in EGFR, The ctDNA study included in our trial confirms data PIK3CA, AKT, or ERBB2, MET amplification [29–34], or from previous studies [19, 20], indicating that roughly transcriptomic mechanisms of resistance [35] play a critical two-thirds of patients receiving anti-EGFR schedules role in intrinsic and acquired anti-EGFR resistance. retain their RAS WT status at disease progression. These The safety profile of P-FOLFIRI treatment was in line are accurately the patients that most likely benefit from with that expected. The incidence rate of grade 3 or diarrhea anti-EGFR re-treatment. ORR (between 6 and 10%) and and acne-like rash reactions were higher with P-FOLFIRI PFS (between 4 and 5 months) in our control arm are than with FOLFIRI alone, as well as the overall grade 3 or 4 within the range of those reported in the literature with adverse events. However, these adverse events were gener- second-line FOLFIRI [21–23] or FOLFIRI plus beva- ally manageable. Regrettably, we did not performed quality cizumab [24] and for the RAS naïve enriched popula- of life questionnaires that would have better assessed the tion treated with FOLFIRI [6]. Therefore, the observed clinical impact of this treatment. 13 2162 Clinical and Translational Oncology (2022) 24:2155–2165 Table 3  Most common adverse events in the safety population (> 10% incidence in either treatment arm) SOC/PT Group A Group B Grade 1 and 2 Grade 3 and 4 Grade 5 Total Grade 1 and 2 Grade 3 and 4 Grade 5 Total Subjects n (%) Subjects n (%) Subjects n (%) Subjects n (%) Subjects n (%) Subjects n (%) Subjects n (%) Subjects n (%) Overall 18 (100.0) 12 (66.7) 1 (5.6) 18 (100.0) 11 (84.6) 7 (53.9) 1 (7.7) 12 (92.3) Anemia 6 (33.3) 1 (5.6) 0 (0.0) 6 (33.3) 4 (30.8) 2 (15.4) 0 (0.0) 6 (46.2) Neutropenia 6 (33.3) 4 (22.2) 0 (0.0) 8 (44.4) 5 (38.5) 3 (23.1) 0 (0.0) 6 (46.2) Constipation 3 (16.7) 0 (0.0) 0 (0.0) 3 (16.7) 4 (30.8) 1 (7.7) 0 (0.0) 4 (30.8) Diarrhea 11 (61.1) 3 (16.7) 0 (0.0) 11 (61.1) 9 (69.2) 1 (7.7) 0 (0.0) 9 (69.2) Intestinal 0 (0.0) 0 (0.0) 1 (5.6) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) perforation Asthenia 9 (50.0) 2 (11.1) 0 (0.0) 9 (50.0) 5 (38.5) 1 (7.7) 0 (0.0) 5 (38.5) Death 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 1 (7.7) Fatigue 3 (16.7) 0 (0.0) 0 (0.0) 3 (16.7) 1 (7.7) 0 (0.0) 0 (0.0) 1 (7.7) Mucosal 5 (27.8) 0 (0.0) 0 (0.0) 5 (27.8) 1 (7.7) 1 (7.7) 0 (0.0) 2 (15.4) inflamma- tion Pyrexia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.7) 1 (7.7) 0 (0.0) 2 (15.4) Folliculitis 2 (11.1) 0 (0.0) 0 (0.0) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Urinary tract 2 (11.1) 0 (0.0) 0 (0.0) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) infection Alanine 2 (11.1) 0 (0.0) 0 (0.0) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) aminotrans- ferase increased Blood 1 (5.6) 1 (5.6) 0 (0.0) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) bilirubin increased Platelet count 1 (5.6) 1 (5.6) 0 (0.0) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) decreased Decreased 4 (22.2) 0 (0.0) 0 (0.0) 4 (22.2) 5 (38.5) 0 (0.0) 0 (0.0) 5 (38.5) appetite Hypokalaemia 0 (0.0) 2 (11.1) 0 (0.0) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Hypomagne- 6 (33.3) 1 (5.6) 0 (0.0) 7 (38.9) 1 (7.7) 0 (0.0) 0 (0.0) 1 (7.7) saemia Back pain 2 (11.1) 0 (0.0) 0 (0.0) 2 (11.1) 1 (7.7) 0 (0.0) 0 (0.0) 1 (7.7) Dysphonia 2 (11.1) 0 (0.0) 0 (0.0) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Dyspnea 3 (16.7) 0 (0.0) 0 (0.0) 3 (16.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Alopecia 3 (16.7) 0 (0.0) 0 (0.0) 3 (16.7) 1 (7.7) 0 (0.0) 0 (0.0) 1 (7.7) Erythema 2 (11.1) 1 (5.6) 0 (0.0) 3 (16.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Onycholysis 2 (11.1) 0 (0.0) 0 (0.0) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Pruritus 2 (11.1) 0 (0.0) 0 (0.0) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Rash 7 (38.9) 2 (11.1) 0 (0.0) 7 (38.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Skin toxicity 4 (22.2) 1 (5.6) 0 (0.0) 4 (22.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Vascular 2 (11.1) 0 (0.0) 0 (0.0) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) disorders Percentages are based on the number of subjects (N) in a given study group or overall as the denominator For each row category, a subject with two or more adverse events in that category is counted only once for the patients column System Organ Class and Preferred Term are based on the Version 18.0 of the MedDRA dictionary Events number of events, Subjects number of subjects Group A FOLFIRI + panitumumab Therapy, Group B FOLFIRI alone Therapy 13 Clinical and Translational Oncology (2022) 24:2155–2165 2163 In conclusion, the BEYOND study suggests a meaningful included in the article's Creative Commons licence, unless indicated clinical benefit of adding panitumumab to FOLFIRI beyond otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not progression to first-line P-FOLFOX in metastatic CRC permitted by statutory regulation or exceeds the permitted use, you will patients with WT RAS status selected by LB at relapse. More need to obtain permission directly from the copyright holder. To view a globally, it also supports the potential value of these novel copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. approaches evaluating anti-EGFR re-treatment (continua- tion or rechallenge) in the second- or third-line treatment. Although the study was closed prematurely, this strategy deserves further investigation. References 1. Cancer incidence and mortality in EU-27 countries. https://​ec.​ europa.e​ u/j​ rc/e​ n/n​ ews/2​ 02-c​ ancer-i​ ncide​ nce-a​ nd-m ​ ortal​ ity-e​ u-2​ 7-​ Funding This work was supported by AMGEN S.A. count​ries. Accessed 10 May 2022. 2. 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Efficacy Research Grants (AGAUR) (2014-SGR-474 and 2017-SGR-1174), of continued cetuximab for unresectable metastatic colorectal Fundació la Marató de TV3 (201330.10), Instituto de Salud Carlos cancer after disease progression during first-line cetuximab- III (PI13/01728 and PI19/00740), Fundacion Olga Torres (Modali- based chemotherapy: a retrospective cohort study. Oncotarget. tat A. 2019/2020), and Spanish Association Against Cancer (AECC, 2016;7:11380–96. PROYE19040POST_001). All remaining authors have declared no 9. Liu X, George GC, Tsimberidou AM, Naing A, Wheler JJ, conflicts of interest. Kopetz S, et al. Retreatment with anti-EGFR based therapies in metastatic colorectal cancer: impact of intervening time interval Ethical approval All procedures performed in studies involving human and prior anti-EGFR response. BMC Cancer. 2015;15:343–50. participants were in accordance with the ethical standards of the insti- 10. 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Lancet Oncol. 2013;14:29–33. 13 Clinical and Translational Oncology (2022) 24:2155–2165 2165 Authors and Affiliations Jorge Aparicio1 · Anna C. Virgili Manrique2 · Jaume Capdevila3,4 · Félix Muñoz Boza5 · Patricia Galván6 · Paula Richart1 · Helena Oliveres6 · David Páez2 · Jorge Hernando3 · Sara Serrano5 · Ruth Vera7 · Xavier Hernandez‑Yagüe8 · Rafael Álvarez Gallego9 · M. Carmen Riesco‑Martinez10 · Xavier García de Albeniz11 · Joan Maurel6 1 7 Medical Oncology Department, Hospital Universitari i Medical Oncology Department, Complejo Hospitalario de Politècnic La Fe, Avda. Abril Martorell 106, 46026 Valencia, Navarra, Pamplona, Spain Spain 8 Medical Oncology Department, ICO, Girona, Girona, Spain 2 Medical Oncology Department, Hospital de la Santa Creu i 9 Medical Oncology Department, Hospital Madrid Norte San Sant Pau, Barcelona, Spain Chinarro-Centro Integral Oncologico Clara Campal, Madrid, 3 Medical Oncology Department, Vall d’Hebron University Spain Hospital, Vall Hebron Institute of Oncology (VHIO), 10 Medical Oncology Department, Hospital Universitario, 12 Barcelona, Spain Octubre, Madrid, Spain 4 IOB-Teknon, Barcelona, Spain 11 RTI Health Solutions, Barcelona, Spain 5 Medical Oncology Department, Hospital Universitari Sant Joan de Reus, Reus, Spain 6 Translational Genomics and Targeted Therapies in Solid Tumors, Medical Oncology Department, Hospital Clínic de Barcelona, C/ Villaroel, 170, 08036 Barcelona, Spain 13