First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: A randomised,phase II trial (PLANET-TTD)

BackgroundIn first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue (KRAS) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves outcomes when added to FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]. However no trial has directly compared these combinations.MethodsMulticentre, open-label study in untreated patients ≥ 18 years with (WT)-KRAS mCRC and multiple or unresectable liver-limited disease (LLD) randomised to either Pmab-FOLFOX4 or Pmab-FOLFIRI. The primary end-point was objective response rate (ORR). Secondary end-points included liver metastases resection rate (R0 + R1), progression-free survival (PFS), overall survival (OS), adverse events and perioperative safety. Exploratory end-points were: response by RAS status, early tumour shrinkage (ETS) and depth of response (DpR) in WT-RAS patients.ResultsData on 77 patients were analysed (38 Pmab-FOLFOX4; 39 Pmab-FOLFIRI; WT-RAS: 27/26, respectively). ORR was 74% with Pmab-FOLFOX4 and 67% with Pmab-FOLFIRI (WT-RAS: 78%/73%). Out of the above, 45% and 59% underwent surgical resection, respectively (WT-RAS: 37%/69%). The R0-R1 resection rate was 34%/46% (WT-RAS:26%/54%). Median PFS was 13/14 months (hazard ratio [HR] Pmab-FOLFIRI versus Pmab-FOLFOX4: 0.9; 95% confidence interval: [0.6–1.5]; WT-RAS:13/15; HR: 0.7 [0.4–1.3]). Median OS was 37/41 months (HR:1.0 [0.6–1.8]; WT-RAS: 39/49; HR:0.9 [0.4–1.9]). In WT-RAS patients with confirmed response, median DpR was 71%/66%, and 65%/77% of patients showed ETS ≥ 30%/ ≥ 20% at week 8, without significant differences between arms; these patients had longer median PFS and OS and higher resectability rates. Surgery was associated with longer survival. Perioperative and overall safety were similar, except for higher grade 3/4 neutropenia (40%/10%; p = 0.003) and neuropathy (13%/0%; p = 0.025) in the Pmab-FOLFOX4 arm.ConclusionsIn patients with WT-KRAS mCRC and LLD, both first-line Pmab-FOLFOX4 and Pmab-FOLFIRI resulted in high ORR and ETS, allowing potentially curative resection. No significant differences in efficacy were observed between the two regimens.(clinicaltrials.gov:NCT00885885).     

Multicenter Single-Arm,Two-Stage Phase 2 Study of Panitumumab in Patients With Cetuximab-Refractory Metastatic Colorectal Cancer: The PACER Trial

PurposeTo assess whether panitumumab is active in patients with cetuximab-refractory metastatic colorectal cancer (mCRC).Patients and MethodsEligible patients had pretreated RAS (renin–angiotensin system) wild-type mCRC that progressed after cetuximab treatment, after having shown either objective response or stable disease. A minimax two-stage design was applied, with progression-free rate at 2 months as the primary end point. At least 12 of 28 and 21 of 41 successes at the first and second stage, respectively, were required for a positive result. Panitumumab 6 mg/kg was provided every 2 weeks, until progression or unacceptable toxicity.ResultsOverall, 52 patients with KRAS (Kirsten rat sarcoma viral oncogene) wild-type disease were enrolled, but 11 were found to have mutated disease after all-RAS retesting. Among 41 eligible patients, median time since diagnosis was 38 months, and 71% experienced an objective response to previous cetuximab. First stage was passed with 12 of 28 patients alive without progression at 2 months. At the second stage, 17 of 41 patients were alive without progression at 2 months. At a median follow-up of 21.8 months, 35 patients experienced disease progression, and 26 died. Median progression-free survival was 2.1 months (95% confidence interval, 1.8-3.6) and median overall survival 6.8 months (95% confidence interval, 4.6-16.6). Most of the patients experienced no adverse reactions; 25% of patients had grade 3 rash.ConclusionAccording to our study design, panitumumab was not effective in patients with cetuximab-refractory RAS wild-type mCRC.     

A multicenter, multinational analysis of mitomycin C in refractory metastatic colorectal cancer

BackgroundA considerable number of metastatic colorectal cancer (mCRC) patients who progress on standard treatment with 5-fluorouracil (5FU), oxaliplatin, irinotecan and monoclonal antibodies, still have adequate performance status and desire further treatment. Mitomycin C (MMC) has been widely used in this context, and despite good tolerability, there are doubts regarding its true benefit.MethodsIn order to assess the activity of MMC in the refractory mCRC setting, we retrospectively evaluated 109 heavily pre-treated patients who received MMC as single agent or in combination for mCRC at three different institutions in two countries.ResultsMedian patient’s age was 54 years old, 57% were male and 94% had performance status ECOG 0 or 1. MMC was used in second line in 11%, third line in 38% and fourth line or beyond in 51% of patients. 58% received MMC combinations, mainly with capecitabine. Grade 3 or 4 toxicity was observed in 5% of patients and 6% required dose reductions. Median time to treatment failure (TTF) was 1.7 months with MMC and 3.6 months on the regimen prior to MMC, with a ratio between these TTF below 1 in 82% of patients. Median survival was only 4.5 months (95% confidence interval (CI) of 3.48–5.56).ConclusionsThis retrospective data represent the largest reported series of unselected refractory mCRC patients treated with MMC. The median survival of 4.5 months is similar to the survival expected for best supportive care. This lack of activity strongly suggests that MMC should not be routinely used in refractory mCRC.     

First-line single-agent panitumumab in frail elderly patients with wild-type KRAS metastatic colorectal cancer and poor prognostic factors: A phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours

BackgroundFrail elderly patients with metastatic colorectal cancer (mCRC) are not candidates for chemotherapy. Monotherapy with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies may be an option for these patients with few systemic toxic effects.Patients and methodsSingle-arm, multicentre, phase II trial including patients ⩾70 years with wild-type (WT) KRAS (exon 2) mCRC, Eastern Cooperative Oncology Group (ECOG) status ⩽ 3, KPC (Köhne Prognostic Classification) – defined intermediate or high risk status, frailty and/or ineligibility for chemotherapy. Patients received panitumumab until progression or unacceptable toxicity. The primary end-point was progression free survival (PFS) rate at 6 months.ResultsThe study included 33 patients (intention-to-treat (ITT) population). Median age: 81 years; sex: 66.7% male; high-risk KPC status: 45.4%. Median treatment duration was 14 weeks and 6-month PFS rate was 36.4% (95% confidence interval (CI): 20.0–52.8). The objective response rate: 9.1% (95% CI: 0–18.9) (all partial responses), and there were 18 stable diseases (54.5%). Median PFS was 4.3 months (95% CI: 2.8–6.4) and median overall survival (OS) was 7.1 months (95% CI: 5.0–12.3). There were no deaths or grade 4–5 adverse events (AEs) related to panitumumab and the most common grade 3-related AE was rash acneiform (15.2%). A significant association between clinical response and RAS status was observed (P = 0.037). In the WT RAS subgroup (WT exons 2, 3, and 4 of KRAS and NRAS, N = 15), 6-month PFS rate was 53.3% (95% CI: 30.1–75.2) and median PFS and OS were 7.9 and 12.3 months, respectively.ConclusionsSingle-agent panitumumab is active and well tolerated and may be a therapeutic option for high-risk frail elderly patients with WT RAS tumours considered not candidates for chemotherapy (clinicaltrials.gov identifier NCT01126112).     

Phase II Trial of Trametinib and Panitumumab in RAS/RAF Wild Type Metastatic Colorectal Cancer

IntroductionMEK inhibition may overcome resistance to EGFR inhibition in patients with RAS wildtype (wt) metastatic colorectal cancer (mCRC). We evaluated antitumor activity of trametinib (MEK1/2 inhibitor) with panitumumab (EGFR monoclonal antibody) in a phase II trial.MethodsPatients with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior anti-EGFR therapy were treated with trametinib 1.5 mg oral daily and panitumumab 4.8 mg/kg IV every 2 weeks. Primary endpoint was clinical benefit rate (CB; CR, PR, or SD ≥24 weeks) by RECIST v1.1. A 2-stage minimax design was used. Serial plasma circulating free DNA (cfDNA) was collected and profiled using Oncomine Lung cfDNA assay.ResultsFourteen patients were enrolled from November 2015 to April 2019. CB rate was 38% (5/13) and median progression free survival (PFS) was 4.4 months (95% CI, 2.9-7.1). Confirmed overall response rate was 38% (5/13). Treatment-related AE (trAE) included acneiform rash (85%), diarrhea (62%), maculopapular rash (54%), mucositis (46%), and others. Dose modifications and interruptions of trametinib occurred in 69% and panitumumab in 54% of patients. The trial did not progress to stage II accrual due to tolerability and short duration of response. RAS or BRAF mutations cfDNA were detected in 3/13 patients (23%) before radiographic disease progression.ConclusionThe addition of trametinib to panitumumab led to a high rate of tumor shrinkage in RAS/RAF wt metastatic colorectal cancer, with poor tolerability due to a high incidence of skin toxicity. Median PFS was similar to panitumumab alone in historical control data.     

FOLFOXIRI-Bevacizumab or FOLFOX-Panitumumab in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer: A Propensity Score-Based Analysis

BackgroundDoublets plus anti‐epidermal growth factor receptors (EGFRs) are the preferred upfront option for patients with left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). Initial therapy with FOLFOXIRI‐bevacizumab is superior to doublets plus bevacizumab independently from primary tumor sidedness and RAS/BRAF status. No randomized comparison between FOLFOXIRI‐bevacizumab versus doublets plus anti‐EGFRs is available in left‐sided RAS/BRAF wild‐type mCRC.Materials and MethodsWe selected patients with left‐sided RAS and BRAF wild‐type mCRC treated with first‐line FOLFOX‐panitumumab or FOLFOXIRI‐bevacizumab in five randomized trials: Valentino, TRIBE, TRIBE2, STEAM, and CHARTA. A propensity score‐based analysis was performed to compare FOLFOXIRI‐bevacizumab with FOLFOX‐panitumumab.ResultsA total of 185 patients received FOLFOX‐panitumumab and 132 received FOLFOXIRI‐bevacizumab. Median progression‐free survival (PFS) and median overall survival (OS) were 13.3 and 33.1 months in the FOLFOXIRI‐bevacizumab group compared with 11.4 and 30.3 months in the FOLFOX‐panitumumab group (propensity score‐adjusted hazard ratio (HR) for PFS, 0.82; 95% confidence interval (CI), 0.64–1.04; p = .11; propensity score‐adjusted HR for OS, 0.80; 95% CI, 0.59–1.08; p = .14). No significant differences in overall response rate and disease control rate were observed. A statistically nonsignificant difference in favor of FOLFOXIRI‐bevacizumab was observed for OS after secondary resection of metastases. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group, with specific regard to grade 3 and 4 neutropenia (48% vs. 26%, adjusted p = .001).ConclusionAlthough randomized comparison is lacking, both FOLFOXIRI‐bevacizumab and FOLFOX‐panitumumab are valuable treatment options in left‐sided RAS/BRAF wild‐type mCRC.Implications for PracticeA propensity score‐based analysis of five trials was performed to compare FOLFOX‐panitumumab versus FOLFOXIRI‐bevacizumab in left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). No significant differences were observed, but FOLFOXIRI‐bevacizumab achieved numerically superior survival outcomes versus FOLFOX‐panitumumab. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group. These observations suggest that although doublet chemotherapy plus anti‐EGFRs remains the preferred treatment in patients with left‐sided RAS/BRAF wild‐type mCRC, FOLFOXIRI‐bevacizumab is a valuable option able to provide similar, if not better, outcomes at the price of a moderate increase in toxicity and may be adopted based on patients’ preference and potential impact on quality of life.     

Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies

BackgroundPrevious studies have reported the prognostic impact of primary tumor sidedness in metastatic colorectal cancer (mCRC) and its influence on cetuximab efficacy. The present retrospective analysis of two panitumumab trials investigated a possible association between tumor sidedness and treatment efficacy in first-line mCRC patients with RAS wild-type (WT) primary tumors.Materials and methodsData from two randomized first-line panitumumab trials were analyzed for treatment outcomes by primary tumor sidedness for RAS WT patients. PRIME (phase 3; NCT00364013) compared panitumumab plus FOLFOX versus FOLFOX alone; PEAK (phase 2; NCT00819780) compared panitumumab plus FOLFOX versus bevacizumab plus FOLFOX. Primary tumors located in the cecum to transverse colon were coded as right-sided, while tumors located from the splenic flexure to rectum were considered left-sided.ResultsTumor sidedness ascertainment (RAS WT population) was 83% (n = 559/675); 78% of patients (n = 435) had left-sided and 22% (n = 124) had right-sided tumors. Patients with right-sided tumors did worse for all efficacy parameters compared with patients with left-sided disease in the RAS WT population and also in the RAS/BRAF WT subgroup. In patients with left-sided tumors, panitumumab provided better outcomes than the comparator treatment, including on median overall survival (PRIME: 30.3 versus 23.6 months, adjusted hazard ratio = 0.73, P = 0.0112; PEAK: 43.4 versus 32.0 months, adjusted hazard ratio = 0.77, P = 0.3125).ConclusionThe results of these retrospective analyses confirm that in RAS WT patients, right-sided primary tumors are associated with worse prognosis than left-sided tumors, regardless of first-line treatment received. RAS WT patients with left-sided tumors derive greater benefit from panitumumab-containing treatment than chemotherapy alone or combined with bevacizumab, including an overall survival advantage (treatment difference: PRIME 6.7 months; PEAK 11.4 months). No final conclusions regarding optimal treatment could be drawn for RAS WT patients with right-sided mCRC due to the relatively low number of paxtients. Further research in this field is warranted.Trial registration (Clinicaltrials.gov)PRIME (NCT00364013), PEAK (NCT00819780).     

Efficacy of panitumumab in older patients with metastatic colorectal cancer: a retrospective analysis using the database of the Hellenic Oncology Research Group (HORG)

Background

Although colorectal cancer (CRC) is a disease of the older patients, older patients are under-represented from randomized trials. Herein we conducted a retrospective analysis for the effect of panitumumab in the management of older patients (≥65?years) patients with metastatic CRC (mCRC) in the Hellenic Oncology Research Group's (HORG) database.

Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials

BackgroundThe use of epidermal growth factor receptor inhibitors to treat metastatic colorectal cancer (mCRC) patients requires prior confirmation of tumour wild type (WT) RAS mutation status (exons 2/3/4 for KRAS or NRAS). This retrospective pooled analysis aims to robustly estimate RAS mutation prevalence and individual variation patterns in mCRC patients.MethodIndividual patient data from five randomised, controlled panitumumab studies (three phase III, one phase II and one phase Ib/II) were pooled for this analysis. The phase III studies included mCRC patients independent of RAS mutation status; the phase II and Ib/II studies included mCRC patients with confirmed WT KRAS exon 2 status. Four studies conducted RAS testing using Sanger sequencing; one study used a combination of next-generation sequencing and Sanger sequencing. In order to assign overall RAS status, the mutation status of all exons 2/3/4 KRAS or NRAS was required to be known.ResultsData from 3196 mCRC patients from 36 countries were included in the analysis. The overall unadjusted RAS mutation prevalence in mCRC patients was 55.9% (95% confidence interval (CI): [53.9–57.9%]), with the following distribution observed: KRAS exon 2 (prevalence 42.6% [40.7–44.5%]); KRAS exon 3 (3.8% [2.9–4.9%]); KRAS exon 4 (6.2% [5.0–7.6%]); NRAS exon 2 (2.9% [2.1–3.9%]); NRAS exon 3 (4.2% [3.2–5.4%]); NRAS exon 4 (0.3% [0.1–0.7%]). Differences in RAS mutation prevalence estimates were observed by study (p = 0.001), gender (p = 0.030), and by country (p = 0.028).ConclusionsThis analysis provides robust estimates of overall RAS mutation prevalence and individual variation patterns in mCRC patients.     

Safety and efficacy of first-line bevacizumab with FOLFOX,XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study

BackgroundBevacizumab significantly improves survival when added to chemotherapy for metastatic colorectal cancer (mCRC). The Bevacizumab Expanded Access Trial (BEAT) evaluated the safety and efficacy of bevacizumab plus first-line chemotherapy in a general cohort of patients with mCRC.Patients and methodsPatients with unresectable mCRC received chemotherapy (physician's choice) plus bevacizumab [5 mg/kg every 2 weeks (5-fluorouracil regimens) or 7.5 mg/kg every 3 weeks (capecitabine regimens)]. The primary end point was safety, including prospective data collection in patients receiving unanticipated surgery during the study. Secondary objectives were progression-free survival (PFS) and overall survival (OS).ResultsThe final analysis comprised 1914 assessable patients (male 58%; median age 59 years). Chemotherapy included 5-fluorouracil/leucovorin (5-FU/LV) + oxaliplatin (29%), irinotecan plus 5-FU/LV (26%), capecitabine plus oxaliplatin (18%) and monotherapy (16%). Serious/grade 3–5 adverse events of interest for bevacizumab included bleeding (3%), gastrointestinal perforation (2%), arterial thromboembolism (1%), hypertension (5.3%), proteinuria (1%) and wound-healing complications (1%). Sixty-day mortality was 3%. Median PFS was 10.8 months [95% confidence interval (CI) 10.4–11.3 months] and median OS reached 22.7 months (95% CI 21.7–23.8 months).ConclusionsThe BEAT study shows that the efficacy and safety profile of bevacizumab in routine clinical practice is consistent with results observed in prospective randomised clinical trials and another large observational study in the United States (BRiTE study).     

A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer

Background:

We assessed the treatment effect of panitumumab plus best supportive care (BSC) vs BSC on overall survival (OS) in patients with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC) and report the first prospective extended RAS analysis in a phase 3 trial.

Methods:

Patients with wild-type KRAS exon 2 mCRC were randomised 1 : 1 to panitumumab (6 mg kg⁻¹ Q2W) plus BSC or BSC. On-study crossover was prohibited. RAS mutation status was determined by central laboratory testing. The primary endpoint was OS in wild-type KRAS exon 2 mCRC; OS in wild-type RAS mCRC (KRAS and NRAS exons 2, 3, and 4) was a secondary endpoint.

Results:

Three hundred seventy seven patients with wild-type KRAS exon 2 mCRC were randomised. Median OS was 10.0 months with panitumumab plus BSC vs 7.4 months with BSC (HR=0.73; 95% CI=0.57–0.93; P=0.0096). RAS ascertainment was 86%. In wild-type RAS mCRC, median OS for panitumumab plus BSC was 10.0 vs 6.9 months for BSC (HR=0.70; 95% CI=0.53–0.93; P=0.0135). Patients with RAS mutations did not benefit from panitumumab (OS HR=0.99; 95% CI=0.49–2.00). No new safety signals were observed.

Conclusions:

Panitumumab significantly improved OS in wild-type KRAS exon 2 mCRC. The effect was more pronounced in wild-type RAS mCRC, validating previous retrospective analyses.     

Sorafenib Plus Irinotecan Combination in Patients With RAS-mutated Metastatic Colorectal Cancer Refractory To Standard Combined Chemotherapies: A Multicenter,Randomized Phase 2 Trial (NEXIRI-2/PRODIGE 27)

BackgroundNo treatment option was available for patients with RAS-mutated (RASmt) metastatic colorectal cancer (mCRC) who progress after standard combined chemotherapies at the time of the study. After promising results in phase II, the aim of the present NEXIRI-2/PRODIGE 27 trial was to assess the 2-month non-progression rate for sorafenib (NEX) plus irinotecan (IRI), that is, NEXIRI, treatment.MethodsPatients with RASmt mCRC after failure of oxaliplatin, IRI, fluoropyrimidines, and bevacizumab were randomized between NEXIRI (IRI 120-180 mg/m² intravenous, D1 = D15 plus oral NEX 400 mg twice a day) versus IRI (180 mg/m²) versus NEX. Primary endpoint was the 2-month non-progression rate. Secondary endpoints included progression-free and overall survival (PFS and OS), safety, and germline cyclin D1 (CCND1) rs9344 polymorphisms analyses.ResultsA total of 173 patients were included, 59 in NEXIRI, 57 in IRI, and 57 in NEX arms. The 2-month non-progression rate was 52.6% (95% confidence interval [CI]: 39%–66%), 21.4% (10%–33%), and 19.3% (9%–30%) for NEXIRI, IRI, and NEX. Median PFS was 3.6 (95% CI: 2–4.2), 1.7 (1.7–1.8), and 2 (1.8–2.3) months and the median OS was 7.2 (5.8–9.4), 6.3 (4.8–8), and 5.6 (3.9–7.7) months for NEXIRI, IRI, and NEX, respectively. For NEXIRI rs9344CCND1 A/A genotype patients, OS was 19.6 months (95% CI: 4.8–not reached). Main grade 3 toxicities included neutropenia, febrile neutropenia, diarrhea, hand-foot syndrome, and hypertension.ConclusionsIn patients with RASmt mCRC who progressed after standard combined chemotherapies, the results of 2-month non-progression rate and median PFS in the NEXIRI arm were in favor of an increase of the time before progression.     

First-in-Human Phase 1b Trial of Quinacrine Plus Capecitabine in Patients With Refractory Metastatic Colorectal Cancer

BackgroundQuinacrine plus a fluoropyrimidine has in vivo efficacy against metastatic colorectal cancer (mCRC). This phase 1b trial evaluated the combination of quinacrine plus capecitabine in patients with treatment-refractory mCRC.Patients and MethodsUsing a modified Simon accelerated titration design, adults with treatment-refractory mCRC were treated with capecitabine 1000 mg/m² twice daily for 14/21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg twice daily, and 200 mg twice daily for 21 days. The primary endpoint was identifying the maximum tolerated dose, determining tolerability and safety. In an expansion cohort, it was overall response rate and time to tumor progression (TTP).ResultsTen patients (median age of 60 years) were treated in phase 1b. The first 2 quinacrine dosing levels were well tolerated. Dose-limiting toxicities were seen in 3 patients treated with quinacrine 200 mg twice daily. Five additional patients tolerated quinacrine 100 mg twice daily without further dose-limiting toxicities, thus establishing the maximum tolerated dose. Seven additional expansion-cohort patients enrolled onto the study before quinacrine manufacturing ceased within the United States. Five patients experienced stable disease, 1 partial response, and 10 disease progression. Median TTP overall was 2.12 months and median overall survival 5.22 months for the 17 patients.ConclusionCapecitabine and quinacrine can be safely administered at the maximum tolerated dose of capecitabine 1000 mg/m² by mouth twice daily on days 1-14 and quinacrine 100 mg by mouth twice daily on days 1-21 of a 21-day cycle in mCRC patients. Although the expansion study was halted early, TTP was in line with other studies of refractory mCRC, suggesting activity of this regimen in heavily pretreated patients.     

Reduced-dose of doublet chemotherapy combined with anti-EGFR antibodies in vulnerable older patients with metastatic colorectal cancer: Data from the REVOLT study

ObjectivesTo assess the toxicity patterns and effectiveness of doublet chemotherapy when administered at reduced doses of 20% (FOLFOX or FOLFIRI) in combination with anti-EGFR antibodies (cetuximab or panitumumab) in old, vulnerable patients with metastatic colorectal cancer (mCRC).Patients and methodsWe performed a retrospective observational study of RAS and BRAF wild-type, vulnerable patients aged ≥70 years with previously untreated mCRC. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsOne hundred and eighteen patients were collected from 14 selected Italian centres. The median age was 75 (range, 70–85). Geriatric screening by G8 tool gave a score ≤ 14 in all patients. In total, 75 and 43 patients received FOLFOX or FOLFIRI, respectively, in combination with panitumumab (53%) or cetuximab (47%). The overall incidence of grade (G) 3–4 neutropenia was 11.8%, and for skin rash 11%. The most frequent adverse events were G1–2 skin rash (49.1%), G1–2 diarrhea (21.1%) and G1–2 nausea (17.7%). The ORR was 57.3%. Stable disease was observed in 29.1% of patients, with a disease control rate of 86.4%. With a median follow-up of 18 months, the median PFS was 10.0 months (95% confidence interval [CI]: 8.5–11.4), while the median OS was 18.0 months (95% CI: 16.0–19.9). No statistically significant difference was observed between the regimens in terms of ORR, PFS (p = 0.908), and OS (p = 0.832).ConclusionThis study shows that with an appropriate design, including reduced doses, vulnerable older patients best tolerate chemotherapy when combined with anti-EGFR antibodies.     

Panitumumab with Irinotecan/Leucovorin/5-Fluorouracil for First-Line Treatment of Metastatic Colorectal Cancer

PurposePanitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor and is indicated for patients with metastatic colorectal cancer (mCRC) who have experienced disease progression after standard chemotherapy. We conducted this phase II study to assess the ability of panitumumab to be administered with first-line irinotecan-containing regimens in patients with mCRC.Patients and MethodsThis was a 2-part multicenter study of panitumumab 2.5 mg/kg weekly with irinotecan, 5-fluorouracil (5-FU), and leucovorin. Part I used bolus 5-FU (IFL), and part 2 used infusional 5-FU (FOLFIRI). Tolerability (measured by grade 3/4 diarrhea) was the primary endpoint. Objective response, progression-free survival, overall survival, and safety were also examined.ResultsNineteen patients in part I and 24 patients in part 2 received panitumumab plus chemotherapy. Grade 3/4 diarrhea occurred in II patients (58%) in part I and 6 patients (25%) in part 2. All patients had a skin-related toxicity (no grade 4 events). Objective response rates were 46% in part I and 42% in part 2. Disease control rates were 74% in part I and 79% in part 2. Median progression-free survival (95% confidence interval) was 5.6 months (4.4–8.3 months) for part I and 10.9 months (7.7–22.5 months) for part 2. Median overall survival (95% confidence interval) was 17 months (13.7 months to not estimable) for part I and 22.5 months (14.4 months to not estimable) for part 2.ConclusionIn patients with mCRC, panitumumab/IFL was not well tolerated. Panitumumab/FOLFIRI was well tolerated, showed promising activity, and is undergoing further investigation.     

FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS,NRAS, HRAS,BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO)

BackgroundThe FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12–13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies.Patients and methodsWe conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², and folinate 200 mg/m² on day 1, followed by fluorouracil 3000 mg/m² as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12–13–61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m² after two of the first three patients reported grade 3–4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab ± fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR).ResultsEighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow-up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7–12.9 months). After amendment, most common grade 3–4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered.ConclusionsAdding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras–BRAF wild-type patients are promising.     

Randomized study of FOLFIRI plus either panitumumab or bevacizumab for wild‐type KRAS colorectal cancer‐WJOG 6210G

This randomized phase II trial compared panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab plus FOLFIRI as second‐line chemotherapy for wild‐type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) and to explore the values of oncogenes in circulating tumor DNA (ctDNA) and serum proteins as predictive biomarkers. Patients with WT KRAS exon 2 mCRC refractory to first‐line chemotherapy containing oxaliplatin and bevacizumab were randomly assigned to panitumumab plus FOLFIRI or bevacizumab plus FOLFIRI. Of 121 randomly assigned patients, 117 were eligible. Median overall survival (OS) for panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI were 16.2 and 13.4 months [hazard ratio (HR), 1.16; 95% CI, 0.76–1.77], respectively. Progression‐free survival (PFS) was also similar (HR, 1.14; 95% CI, 0.78–1.66). KRAS, NRAS, and BRAF status using ctDNA was successfully examined in 109 patients, and mutations were identified in 19 patients (17.4%). Panitumumab plus FOLFIRI showed favorable survival compared with bevacizumab plus FOLFIRI in WT patients and unfavorable survival in those with mutations (P for interaction = 0.026 in OS and 0.054 in PFS). OS with bevacizumab plus FOLFIRI was better than panitumumab plus FOLFIRI in patients with high serum vascular endothelial growth factor‐A (VEGF‐A) levels and worse in those with low levels (P for interaction = 0.016). Second‐line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC. RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab.