RAS Amplification as a Negative Predictor of Benefit from Anti-EGFR–Containing Therapy Regimens in Metastatic Colorectal Cancer

Background RAS short variant (SV) mutations in colorectal cancer (CRC) are associated with lack of benefit from epidermal growth factor receptor (EGFR) monoclonal antibody (EGFRmAb). However, the clinical implications for RAS amplification (RASa) as a biomarker for anti‐EGFR therapy in CRC remain ill defined.MethodsGenomic analysis was performed using the Foundation Medicine (FM) comprehensive genomic profiling database of 37,233 CRC cases. Clinical outcomes were assessed using two independent cohorts: the City of Hope (COH) cohort of 338 patients with metastatic CRC (mCRC) and the Flatiron Health–FM real‐world clinicogenomic database (CGDB) of 3,904 patients with mCRC.Results RASa was detected in 1.6% (614/37,233) of primarily mCRC. RASa 6–9 (n = 241, 39%), 10–19 (n = 165, 27%), and ≥ 20 (n = 209, 34%) copy number subsets had co‐RAS SV/BRAF V600E in 63%/3%, 31%/0.6%, and 4.8%/0% of cases, respectively. In the COH cohort, six patients with RASa (13–54 copies) received EGFRmAb, four of six had progressive disease, two had stable disease, and median time to treatment discontinuation (TTD) was 2.5 months. Of the CGDB EGFRmAb‐treated patients, those with RASa (n = 9) had median TTD of 4.7 months and overall survival (OS) of 11.4 months, those with RAS SV (n = 101) had median TTD and OS of 5.3 and 9.4 months, and those with RAS/BRAF wild‐type (n = 608) had median TTD and OS of 7.6 and 13.7 months.ConclusionPatients with RASa without RAS mutations (1.1% of mCRC) may have poor outcomes on EGFRmAb, although numbers herein were small, and interpretation is confounded by combination chemotherapy. Larger independent studies are warranted to determine if RASa, including degree of amplification, may act similarly to RAS mutation as a resistance mechanism to EGFRmAb therapies.Implications for PracticeGenomic data suggest that RAS amplification occurs as the sole RAS/RAF alteration in >1% of colorectal cancer cases and that degree of amplification inversely correlates with co‐occurring MAPK pathway alterations. Preliminary clinical evidence suggests that RAS amplification may function similarly to RAS mutation as a negative predictor of benefit from anti‐epidermal growth factor receptor therapies in colorectal cancer. More clinical data are needed, and comprehensive genomic profiling, including detection of RAS amplification, should be used in trial design to inform therapy selection.     

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).     

Cost-effectiveness analysis of panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6 for first-line treatment of patients with wild-type RAS metastatic colorectal cancer

ObjectiveTo investigate the cost-effectiveness of panitumumab plus mFOLFOX6 (oxaliplatin, 5-fluorouracil and leucovorin) compared with bevacizumab plus mFOLFOX6 in first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC).DesignA semi-Markov model was constructed from a French health collective perspective, with health states related to first-line treatment (progression-free), disease progression with and without subsequent active treatment, resection of metastases, disease-free after successful resection and death.MethodsParametric survival analyses of patient-level progression-free and overall survival data from the only head-to-head clinical trial of panitumumab and bevacizumab (PEAK) were performed to estimate transitions to disease progression and death. Additional data from PEAK informed the amount of each drug consumed, duration of therapy, subsequent therapy use, and toxicities related to mCRC treatment. Literature and French public data sources were used to estimate unit costs associated with treatment and duration of subsequent active therapies. Utility weights were calculated from patient-level data from panitumumab trials in the first-, second- and third-line settings. A life-time perspective was applied. Scenario, one-way, and probabilistic sensitivity analyses were performed.ResultsBased on a head-to-head clinical trial that demonstrates better efficacy outcomes for patients with wild-type RAS mCRC who receive panitumumab plus mFOLFOX6 versus bevacizumab plus mFOLFOX6, the incremental cost per life-year gained was estimated to be €26,918, and the incremental cost per quality-adjusted life year (QALY) gained was estimated to be €36,577. Sensitivity analyses indicate the model is robust to alternative parameters and assumptions.ConclusionsThe incremental cost per QALY gained indicates that panitumumab plus mFOLFOX6 represents good value for money in comparison to bevacizumab plus mFOLFOX6 and, with a willingness-to-pay ranging from €40,000 to €60,000, can be considered cost-effective in first-line treatment of patients with wild-type RAS mCRC.     

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.     

Wild-type APC Is Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer

BackgroundThe prognostic implication of wild‐type APC (APC‐WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined.Materials and Methods APC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC).ResultsIn comparison with the APC‐mutant (APC‐MT) population (n = 255), APC‐WT patients (n = 86) tended to be younger (59% of age < 40 vs. 26% of age > 50), right‐sided (41.7% vs. 27%), BRAF ^V600E mutated (23.3% vs. 0.8%), and KRAS wild type (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1, were over‐represented in the APC‐WT versus APC‐MT population (7% vs. 0.4% and 4.7% vs. 0.4%, respectively). APC‐WT patients had a worse overall survival (OS) than APC‐MT patients (22.6 vs. 45.6 months, p < .0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC‐WT was predictive of poor survival (APC‐MT vs. APC‐WT, hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44–0.86, p = .0037). The prognostic implication of APC‐WT on OS was confirmed further in a similar multivariate model of 934 stage IV patients from MSKCC public database (APC‐MT vs. APC‐WT, HR, 0.63, 95% CI, 0.49–0.81, p < .0001).Conclusion APC‐WT is associated with poor OS in MSS mCRC regardless of RAS and BRAF status. Compared with APC‐MT mCRC tumors, APC‐WT tumors were associated with other Wnt activating alterations, including RNF43 and CTNBB1. Our data suggest alternative therapy needs to be investigated in APC‐WT patients.Implications for PracticePatients with microsatellite stable metastatic colorectal cancer with wild‐type APC had a worse overall survival than patients with mutated APC regardless of RAS/RAF status. APC status should be considered as a stratification factor in prospective trials, and novel therapeutic strategies need to be developed for this subgroup of patients.     

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.     

Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO

BackgroundRight-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status.Patients and methodsPatients were randomized to receive upfront 5-fluoruracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or 5-fluoruracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab. Tumors were defined as right- or left-sided if they originated from the caecum to the transverse colon or within the splenic flexure and beyond, respectively. Patients with available information about both primary sidedness and RAS and BRAF status were included in the present analysis. Progression-free survival (PFS), overall survival (OS) and RECIST response rate were assessed according to tumor location and RAS and BRAF mutational status.ResultsInformation about primary sidedness and RAS and BRAF status was available for 358 (70.5%) out of 508 randomized patients. Patients with right-sided tumors (N = 173) presented shorter OS [23.7 versus 31.0 months, HR = 1.42 (95% CI 1.09–1.84), P = 0.010] and a trend toward shorter PFS [10.2 versus 11.5 months, HR = 1.24 (95% CI: 0.98–1.56), P = 0.083] than those with left-sided tumors (N = 185), but these associations were no longer evident when adjusting for RAS and BRAF status. Patients with right-sided tumors achieved more relative benefit from the intensification of the chemotherapy backbone in terms of both PFS (HR = 0.59 versus 0.89, P for interaction = 0.099) and OS (HR = 0.56 versus 0.99, P for interaction = 0.030) and this advantage was independent of their RAS and BRAF status.ConclusionsFOLFOXIRI plus bevacizumab may be regarded as a preferred first-line treatment option for clinically selected patients with right-sided metastatic colorectal cancer irrespective of their RAS and BRAF mutational status. Trial registration: clinicaltrials.gov identifier NCT00719797.     

Survival Outcomes in Patients With RAS Wild Type Metastatic Colorectal Cancer Classified According to Köhne Prognostic Category and BRAF Mutation Status

Background

Köhne prognostic score is used to classify patients with metastatic colorectal cancer (mCRC) as high, intermediate, or low risk. Using data from 2 phase III trials, we analyzed survival in patients categorized according to Köhne prognostic category and virus-induced rapidly accelerated fibrosarcoma murine sarcoma viral oncogene homolog B (BRAF) mutation.

A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer

BackgroundHead-to-head trials comparing first-line epidermal growth factor receptor inhibitor (EGFRI) versus vascular endothelial growth factor inhibitor (bevacizumab) therapy yielded differing results, and debate remains over optimal first-line therapy for patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC).MethodsA PubMed search identified first-line mCRC trials comparing EGFRI plus chemotherapy versus bevacizumab plus chemotherapy; data were subsequently updated using recent congress presentations. This study-level meta-analysis estimated the overall survival (OS) treatment effect of first-line chemotherapy plus EGFRIs or bevacizumab in patients with RAS WT mCRC. Secondary end-points were progression-free survival (PFS), objective response rate (ORR), resection rate and safety. Early tumour shrinkage (ETS) of ≥20% at week 8 was an exploratory end-point.ResultsThree trials comprising data from 1096 patients with RAS WT mCRC were included. OS (hazard ratio [HR]: 0.80 [95% confidence interval: 0.68–0.93]), ORR (odds ratio [OR]: 0.57) and ETS (OR: 0.48) favoured EGFRIs plus chemotherapy versus bevacizumab plus chemotherapy. PFS (HR: 0.98) and resections (OR: 0.93) were similar between treatments. For patients with KRAS exon 2 WT/‘other’ RAS mutant mCRC the OS HR was 0.70. A safety meta-analysis was not possible due to a lack of data; in the individual studies, skin toxicities and hypomagnesaemia were more common with EGFRIs, nausea and hypertension were more common with bevacizumab.ConclusionsThis meta-analysis supports a potential benefit for first-line EGFRI plus chemotherapy versus bevacizumab plus chemotherapy with respect to OS, ORR and ETS in patients with RAS WT mCRC. A patient-level meta-analysis is awaited.     

Impact of Primary Tumor Location on Survival After Curative Resection in Patients with Colon Cancer: A Meta-Analysis of Propensity Score-Matching Studies

BackgroundRecent retrospective subgroup analyses of patients with unresectable colon cancer (CC) receiving systemic chemotherapy have demonstrated that there is a significant difference in treatment outcome between patients with right‐sided CC (RSCC) and those with left‐sided CC (LSCC). However, it is impossible to divide patients with CC randomly into RSCC and LSCC groups before surgery. Therefore, the aim of this study is to explore the impact of primary tumor location (PTL) on survival after curative surgery for patients with CC using propensity score‐matching (PSM) studies instead of randomization.Materials and MethodsWe performed a comprehensive electronic search of the literature up to January 2019 to identify studies that had used databases allowing comparison of postoperative survival between patients with RSCC and those with LSCC. To integrate the impact of PTL on 5‐year overall survival (OS) after curative surgery, a meta‐analysis was performed using random‐effects models to calculate the risk ratio (RR) and 95% confidence interval (CI) for the selected PSM studies.ResultsFive studies involving a total of 398,687 patients with CC were included in this meta‐analysis. Among 205,641 patients with RSCC, 69,091 (33.6%) died during the observation period, whereas among 193,046 patients with LSCC, 63,380 (32.8%) died during the same period. These results revealed that patients with RSCC and those with LSCC had almost the same 5‐year OS (RR, 0.98; 95% CI, 0.89–1.07; p = .64; I ² = 97%).ConclusionThis meta‐analysis has demonstrated that there was no significant difference in 5‐year OS between patients with RSCC and those with LSCC after curative resection.Implications for PracticeTo integrate the impact of primary tumor location (PTL) on 5‐year overall survival (OS) after curative surgery, five propensity score‐matching (PSM) studies involving a total of 398,687 patients with colon cancer (CC) were included in this meta‐analysis. Among 205,641 patients with right‐sided CC (RSCC), 69,091 (33.6%) died during the observation period, whereas among 193,046 patients with left‐sided CC (LSCC), 63,380 (32.8%) died during the same period. These results revealed that patients with RSCC and those with LSCC had almost the same 5‐year OS (risk ratio, 0.98; 95% confidence interval, 0.89–1.07; p = .64; I² = 97%).     

Rationale and Study Design of the PARERE Trial: Randomized phase II Study of Panitumumab Re-Treatment Followed by Regorafenib Versus the Reverse Sequence in RAS and BRAF Wild-Type Chemo-Refractory Metastatic Colorectal Cancer Patients

BackgroundA recent phase II randomized Japanese study reported better survival with regorafenib followed at progression by cetuximab ± irinotecan compared with the reverse standard sequence in chemo-refractory and anti-EGFR-naïve, RAS wild-type (wt) mCRC patients. Nowadays the use of anti-EGFR antibodies is more frequently anticipated to the first-line of therapy especially in patients with left-sided RAS/BRAF wt tumours. However, retrospective analyses and phase II single-arm trials showed promising activity of re-using anti-EGFRs in metastatic colorectal cancer (mCRC) patients who previously achieved benefit from a first-line anti-EGFR-based treatment. Post-hoc analyses of these trials revealed that the detection of RAS mutations in circulating tumour DNA (ct-DNA) at the time of re-treatment may be useful to identify resistant patients.Patients and MethodsPARERE (NCT04787341) is a prospective, open label, multicentre phase II study in which 214 RAS/BRAF wt chemo-refractory mCRC patients with previous benefit from first-line anti-EGFR-based treatment and RAS/BRAF wt ct-DNA in the liquid biopsy collected at the time of inclusion will be randomized in a 1:1 ratio to receive panitumumab followed after progression by regorafenib versus the reverse sequence. Primary endpoint is overall survival. Secondary endpoints are 1st-progression free-survival (PFS), 2nd-PFS, time to failure strategy, objective response rate, and safety.Aim of the studyThe aim of this study is to validate the role of anti-EGFR retreatment and its proper placement in the therapeutic route of mCRC patients selected according to the analysis of ct-DNA in liquid biopsy. Results are expected at the end of 2023.     

FOLFOXIRI or FOLFOXIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: a propensity score-adjusted analysis from two randomized clinical trials

BackgroundFOLFOXIRI plus bevacizumab is a valid option as upfront treatment for metastatic colorectal cancer (mCRC) patients. While several trials investigated the effect of combining bevacizumab with different chemotherapy regimens, including fluoropyrimidines monotherapy and oxaliplatin- or irinotecan-containing doublets, no randomized comparison assessing the impact of the addition of bevacizumab to FOLFOXIRI is available.Patients and methodsA total of 122 mCRC patients received first-line FOLFOXIRI in the phase III trial by the GONO (FOLFOXIRI group) and 252 patients received first-line FOLFOXIRI plus bevacizumab in the TRIBE trial (FOLFOXIRI plus bevacizumab group). A propensity score-adjusted method was adopted to provide an estimation of the benefit from the addition of bevacizumab to FOLFOXIRI in terms of survival and activity parameters.ResultsPatients in the FOLFOXIRI group had more frequently Eastern Cooperative Oncology Group performance status of one or two, high Köhne score, metachronous and liver-limited disease, had previously received adjuvant treatments and had their primary tumors resected. The median progression-free survival (PFS) was 12.3 months in the FOLFOXIRI plus bevacizumab group compared with 10.0 months in the FOLFOXIRI group {propensity score-adjusted hazard ratio (HR) 0.74 [95% confidence interval (CI) 0.59–0.94], P = 0.013}. This association was significant also in the multivariable model (P = 0.024). The median OS was 29.8 months in the FOLFOXIRI plus bevacizumab group compared with 23.6 months in the FOLFOXIRI group [propensity score-adjusted HR: 0.72 (95% CI 0.56–0.93), P = 0.014]. At the multivariable model, the addition of bevacizumab was still associated with significantly longer OS (P = 0.030). No significant differences in RECIST response rate (RR) [65.1% versus 55.7%; propensity score-adjusted odds ratio (OR): 1.29 (95% CI 0.81–2.05), P = 0.280], early RR [62.7% versus 57.8%; OR: 1.14 (95% CI 0.68–1.93), P = 0.619] and median depth of response (42.2% versus 53.8%, P = 0.259) were reported.ConclusionsThough in the absence of a randomized comparison, the addition of bevacizumab to FOLFOXIRI provides significant benefit in PFS and OS, thus supporting the use of FOLFOXIRI plus bevacizumab as upfront treatment for mCRC patients.Trials&rsquo; numbersNCT01219920 and NCT00719797     

Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer

BackgroundHere we present updated survival of the CAIRO2 trial and assessed whether the addition of anti-EGFR to anti-VEGF therapy could still be an effective treatment option for patients with extended RAS/BRAF wildtype and left-sided metastatic colorectal cancer (mCRC).Materials and MethodsRetrospective updated survival and extended RAS and BRAF V600E mutational analysis were performed in the CAIRO2 trial, a multicenter, randomized phase III trial on the effect of adding cetuximab to a combination of capecitabine, oxaliplatin (CAPOX), and bevacizumab in mCRC.ResultsUpdated survival analysis confirmed that the addition of cetuximab did not provide a benefit on either progression free (PFS) or overall survival (OS) in the intention-to-treat population. With the extended mutational analyses 31 KRAS, 31 NRAS and 12 BRAF V600E additional mutations were found. No benefit of the addition of cetuximab was observed within the extended wildtype group, even when selecting only left-sided tumors (PFS HR 0.96, p = 0.7775). However, compared to the original trial an increase of 6.5 months was seen for patients with both extended wildtype and left-sided tumors (median OS 28.6 months).ConclusionAdding cetuximab to CAPOX and bevacizumab does not provide clinical benefit in patients with mCRC, even in the extended wildtype group with left-sided tumors. However, in the extended wildtype group we did observe clinically relevant higher survival compared to the initial trial report, indicating that it is important to analyze a broader panel of RAS and BRAF variants using more recent sequencing techniques when assessing survival benefit after anti-EGFR therapy.     

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.     

Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer

Introduction

Tumor rat sarcoma gene (RAS) status is a negative predictive biomarker for anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). We analyzed outcomes according to RAS and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutational status, and evaluated early tumor shrinkage (ETS) and depth of response (DpR) for patients with wild type RAS.

Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study

BackgroundRAS and BRAF mutations have been identified as negative prognostic factors in metastatic colorectal cancer. Efficacy of 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) plus bevacizumab in patients with RAS-mutant tumours needs to be further evaluated. Whether to treat patients with BRAF-mutant tumours with either bevacizumab or anti-epidermal growth factor receptor (EGFR) antibodies remains unclear.MethodsPatients treated within the FIRE-3 trial were retrospectively tested for BRAF and RAS mutations using formalin fixated paraffin embedded (FFPE) tumour material applying pyrosequencing for KRAS and NRAS exon 2, 3 and 4 mutations as far as for BRAF mutations. Survival analysis was done using Kaplan–Meier estimation and differences were expressed using the log-rank test. Overall response rate (ORR) was compared using Fisher's exact test. Data from a central independent radiological response evaluation were used to calculate early tumour shrinkage (ETS) and depth of response (DpR).ResultsOverall, 188 patients with RAS-mutant tumours and 48 with BRAF-mutant tumours were identified. In BRAF-mutant patients, ORR was numerically higher in the cetuximab versus the bevacizumab arm (52% versus 40%), while comparable results were achieved for progression-free survival (PFS; hazard ratio [HR] = 0.84, p = 0.56) and overall survival (OS; HR 0.79, p = 0.45). RAS mutation was associated with a trend towards lower ORR (37% versus 50.5%, p = 0.11) and shorter PFS (7.4 versus 9.7 months; HR 1.25; p = 0.14) in patients receiving FOLFIRI plus cetuximab versus bevacizumab, but OS was comparable (19.1 versus 20.1 months; HR 1.05; p = 0.73), respectively. ETS identified subgroups sensitive to cetuximab-based treatment in both BRAF- (9/17) and RAS-mutant (18/48) patients and was associated with significantly longer OS. DpR was comparable between both treatment arms in RAS- and BRAF-mutant patients, respectively.ConclusionsIn BRAF- and RAS-mutant patients, cetuximab- and bevacizumab-based treatment had comparable survival times. ETS represents an early parameter associated with the benefit from anti-EGFR, while this was not the case with vascular endothelial growth factor A blockade.     

Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study

BackgroundThe phase 3 CAIRO3 study showed that capecitabine plus bevacizumab (CAP-B) maintenance treatment after six cycles capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in metastatic colorectal cancer (mCRC) patients is effective, without compromising quality of life. In this post hoc analysis with updated follow-up and data regarding sidedness, we defined subgroups according to RAS/BRAF mutation status and mismatch repair (MMR) status, and investigated their influence on treatment efficacy.Patients and methodsA total of 558 patients with previously untreated mCRC and stable disease or better after six cycles CAPOX-B induction treatment were randomised to either CAP-B maintenance treatment (n = 279) or observation (n = 279). Upon first progression, patients were to receive CAPOX-B reintroduction until second progression (PFS2, primary end point). We centrally assessed RAS/BRAF mutation status and MMR status, or used local results if central assessment was not possible. Intention-to-treat stratified Cox models adjusted for baseline covariables were used to examine whether treatment efficacy was modified by RAS/BRAF mutation status.ResultsRAS, BRAF mutations, and MMR deficiency were detected in 240/420 (58%), 36/381 (9%), and 4/279 (1%) patients, respectively. At a median follow-up of 87 months (IQR 69–97), all mutational subgroups showed significant improvement from maintenance treatment for the primary end point PFS2 [RAS/BRAF wild-type: hazard ratio (HR) 0.57 (95% CI 0.39–0.84); RAS-mutant: HR 0.74 (0.55–0.98); ^V600EBRAF-mutant: HR 0.28 (0.12–0.64)] and secondary end points, except for the RAS-mutant subgroup regarding overall survival. Adjustment for sidedness instead of primary tumour location yielded comparable results. Although right-sided tumours were associated with inferior prognosis, both patients with right- and left-sided tumours showed significant benefit from maintenance treatment.ConclusionsCAP-B maintenance treatment after six cycles CAPOX-B is effective in first-line treatment of mCRC across all mutational subgroups. The benefit of maintenance treatment was most pronounced in patients with RAS/BRAF wild-type and ^V600EBRAF-mutant tumours.ClinicalTrials.gov numberNCT00442637.     

FOLFOXIRI plus Bevacizumab Versus FOLFOX plus Panitumumab for Metastatic Left‐Sided RAS/BRAF Wild‐Type Colorectal Cancer: Which “Side” Are You On?

This commentary focuses on the results of the study by Pietrantonio et al., which evaluated the clinical conundrum of triplet versus doublet chemotherapy in combination with targeted therapy for metastatic left-sided RAS/BRAF wild-type colorectal cancer and appears in this issue. Both FOLFOXIRI [fluorouracil, leucovorin, oxaliplatin, and irinotecan] plus bevacizumab and FOLFOX [fluorouracil, leucovorin, and oxaliplatin] plus panitumumab have shown impressive activity in this population; however, the two have not been directly compared. The article by Pietrantonio et al. presents a propensity score-adjusted analysis using information from five previous randomized trials and provides best available evidence comparing these regimens. This commentary will discuss their results and how their findings fit in current treatment paradigms.     

Resectability,conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study

Background Outcomes after metastasectomy for metastatic colorectal cancer (mCRC) vary with RAS and BRAF mutational status, but their effects on resectability and conversion rates have not been extensively studied.Methods This substudy of the prospective RAXO trial included 906 patients recruited between 2011 and 2018. We evaluated repeated centralised resectability assessment, conversion/resection rates and overall survival (OS), according to RAS and BRAF status.Results Patients included 289 with RAS and BRAF wild-type (RAS and BRAFwt), 529 with RAS mutated (RASmt) and 88 with BRAF mutated (BRAFmt) mCRC. Metastatic prevalence varied between the RAS and BRAFwt/RASmt/BRAFmt groups, for liver (78%/74%/61%), lung (24%/35%/28%) and peritoneal (15%/15%/32%) metastases, respectively. Upfront resectability (32%/29%/15%), conversion (16%/13%/7%) and resection/local ablative therapy (LAT) rates (45%/37%/17%) varied for RASa and BRAFwt/RASmt/BRAFmt, respectively. Median OS for patients treated with resection/LAT (n = 342) was 83/69/30 months, with 5-year OS-rates of 67%/60%/24%, while systemic therapy-only patients (n = 564) had OS of 29/21/15 months with 5-year OS-rates of 11%/6%/2% in RAS and BRAFwt/RASmt/BRAFmt, respectively. Resection/LAT was associated with improved OS in all subgroups.Conclusions There were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status.Clinical trial registration {"type":"clinical-trial","attrs":{"text":"NCT01531621","term_id":"NCT01531621"}}NCT01531621/EudraCT2011-003158-24Subject terms: Metastasis, Colorectal cancer, Surgical oncology, Prognostic markers     

Phase II Study of Panitumumab Monotherapy in Chemotherapy‐Naïve Frail or Elderly Patients with Unresectable RAS Wild‐Type Colorectal Cancer: OGSG 1602

Lessons Learned

• Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild‐type unresectable colorectal cancer.
• It is especially effective for left‐sided tumors; therefore, panitumumab as first‐line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin‐based or irinotecan‐based combination regimens.

BackgroundFirst‐line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy‐naïve frail or elderly patients with unresectable RAS wild‐type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first‐line treatment.MethodsWe conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities.ResultsThirty‐six patients (median age: 81 [range, 67–88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty‐three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty‐eight patients (77.8%) had left‐sided CRC, whereas eight (22.2%) had right‐sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4–67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5–87.7). The RR of patients with left‐ and right‐sided tumors was 65.4% (95% CI, 44.3–82.8) and 0.0% (95% CI, 0.0–36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%).ConclusionPanitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress.