Panitumumab

Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.

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Background

Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients.

Methods

This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m2 on day 1 of each cycle) and fluorouracil (1000 mg/m2 on days 1—4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov, number NCT00460265.

Findings

Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8—12·2) in the panitumumab group and 9·0 months (8·1—11·2) in the control group (hazard ratio [HR] 0·873, 95% CI 0·729—1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6—6·6) in the panitumumab group and 4·6 months (4·1—5·4) in the control group (HR 0·780, 95% CI 0·659—0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months [95% CI 9·7—13·7] vs8·6 months [6·9—11·1]; HR 0·73 [95% CI 0·58—0·93]; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months [7·3—12·9] vs 12·6 months [7·7—17·4]; 1·00 [0·62—1·61]; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 [95% CI 0·47—1·04]).

Interpretation

Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings.

Source: Lancet

Panitumumab Fails to Improve Outcome in Esophagogastric Cancer.

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Adding panitumumab to chemotherapy resulted in significantly shorter overall survival.

 

For patients with adenocarcinomas of the esophagus and stomach, conventional 5-fluorouracil (5-FU) plus platinum-based chemotherapy achieves an overall survival of only 9 to 11 months. The only targeted therapy approved for this disease is trastuzumab, which improves response and survival when combined with chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic disease (JW Oncol Hematol Sep 14 2010).

Investigators from the U.K. now report the results of an industry-funded, open-label, multicenter, randomized, phase III trial of the epidermal growth factor receptor (EGFR)-targeted agent panitumumab plus chemotherapy for untreated metastatic esophagogastric cancer. Patients received either EOC: epirubicin (50 mg/m2), oxaliplatin (130 mg/m2), and capecitabine (1250 mg/m2/day for 21 days) cycled every 3 weeks; or modified EOC plus panitumumab: epirubicin (50 mg/m2), oxaliplatin (100 mg/m2), and capecitabine (1000 mg/m2/day for 21 days) plus panitumumab (9 mg/kg) cycled every 3 weeks.

Of 1000 planned patients, only 553 were treated due to early trial closure after an interim analysis showed inferior overall survival with modified EOC plus panitumumab. Most patients treated were male (82%–83%), were age 60 or older (60%–62%), and had performance status 1 (52%) and cancers of the esophagus (38%–40%) or gastroesophageal junction (27%–34%).

Although rates of response were equivalent in the two treatment arms (42%–46%), modified EOC plus panitumumab resulted in inferior overall survival (the primary endpoint; 8.8 vs. 11.3 months; HR 1.37; P=0.013) and a trend toward inferior progression-free survival (6.0 vs. 7.4 months; HR 1.22; P=0.068). Modified EOC plus panitumumab resulted in more grade 3 or 4 diarrhea, mucositis, and skin rash, but less grade 3 or 4 neuropathy and hematologic toxicity, likely due to a shorter duration of therapy.

Comment: This large, randomized trial in unselected patients with advanced esophagogastric cancer indicates that the addition of panitumumab to chemotherapy has a deleterious effect on patient outcomes. These findings are consistent with those simultaneously reported for cetuximab (JW Oncol Hematol May 28 2013).Given these strikingly negative results, interest in further study of potential EGFR-targeted therapies for esophagogastric cancer will likely diminish, and the possibility of discovering a biomarker to identify patients who might benefit from such treatments is unlikely.

 

Source: Journal Watch Oncology and Hematology

 

 

 

Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.

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Background

EGFR overexpression occurs in 27—55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma.

Methods

In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1—21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1—21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785.

Findings

Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6—13·0) compared with 8·8 months (7·7—9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07—1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3—4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 [13%] vs 74 [28%]).

Interpretation

Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma.

Discussion

The REAL3 trial is one of two concurrent randomised phase 3 trials (the other being the EXPAND trial15) assessing the addition of anti-EGFR monoclonal antibodies to chemotherapy in first-line oesophagogastric cancer. Based on the findings of REAL3, use of panitumumab in combination with EOC cannot be recommended in an unselected population with advanced oesophagogastric adenocarcinoma, and was associated with inferior overall survival and PFS. Notably, this detrimental outcome in the experimental group was not predicted by the phase 2 endpoint of response rate (overall response rate 52% with mEOC+P). This trial does, however, confirm the efficacy of the EOC control group in this setting, with median overall survival and PFS results that are consistent with those previously reported in REAL2 (11·2 months for overall survival and 7·0 months for PFS).3

The poor outcome associated with mEOC+P in this trial did not seem to be attributable to increased treatment-related deaths, and therefore other potential explanations for our findings need to be considered. First, as reported previously,12combination of panitumumab with full-dose EOC in the initial stages of the trial was associated with unacceptably high rates of grade 3 diarrhoea (four of the first five patients by cycle four). Therefore, we had to reduce the starting doses of oxaliplatin (by 23%) and capecitabine (by 20%) in the experimental group. Although these changes undoubtedly reduced the frequency of grade 3—4 diarrhoea with mEOC+P (17% in phase 3 population), they also served to reduce the dose intensity of chemotherapy, which is reflected in the reduced incidence of grade 3—4 neutropenia and peripheral neuropathy noted in the mEOC+P group. Additionally, the dose intensity data show a reduced proportion of patients achieving at least 80% of the planned capecitabine dose in the experimental group, suggesting that mEOC+P was still slightly more difficult to deliver than standard EOC.

Second, a negative interaction might have occurred between panitumumab and one or more of the EOC components. Evidence in the setting of colorectal cancer suggests that the chemotherapy partner for anti-EGFR therapy might be an important determinant of treatment efficacy, with oxaliplatin-containing regimens yielding inconsistent results. The OPUS16and PRIME11 studies provide evidence of improved outcomes with the addition of cetuximab and panitumumab respectively, whereas no benefit was associated with the addition of cetuximab in the COIN17 and NORDIC VII18 studies in the same setting. Recent cell-line data also suggest that greater synergy might exist between anti-EGFR therapy and irinotecan than with oxaliplatin.19 Additionally, the COIN trial17 results suggest that there might be a differential benefit from cetuximab dependent on the fluoropyrimidine partner, with patients receiving oxaliplatin plus fluorouracil seemingly deriving increased benefit compared with those treated with oxaliplatin plus capecitabine. At present, the significance of these potential interactions is unknown, and has not been assessed in the setting of oesophagogastric cancer.

Third, our findings might have been affected because we assessed panitumumab therapy in a molecularly unselected population. During the years since the inception of the REAL3 trial, several studies have advanced our understanding of the EGFR signalling pathway and its role in oesophagogastric adenocarcinoma. Hot-spot mutations in key oncogenic drivers such as KRAS (common in colorectal cancer) and BRAF (common in malignant melanoma) are now known to be infrequent molecular events in oesophagogastric adenocarcinoma. Indeed, the 5·7% frequency of KRAS mutation in our population is in keeping with the 3—10% reported in other studies,20—22 and we did not note any BRAF mutations in 167 tumour samples tested. By contrast, gene copy number alterations (amplifications and deletions) seem to be a relatively frequent finding in oesophagogastric adenocarcinoma and are more likely to represent the key molecular alterations driving carcinogenesis. Two recent series23, 24 of detailed genomic analyses in oesophagogastric adenocarcinoma reported that about 37% of tumours harbour copy number aberrations in genes that are deemed to be targetable, including KRAS, EGFR, HER2, and MET. Randomised clinical trials are therefore needed to establish whether targeting of these oncogenic signal transduction pathways can meaningfully improve outcomes for patients.

In preclinical studies, cetuximab can decrease EGFR pathway signalling via reduced phosphorylation of EGFR and AKT in oesophagogastric cancer cell lines.25 In combination with chemotherapy, cetuximab results in synergistic inhibition of cell proliferation and enhanced apoptosis.25—27 In hypoxic gastric cancer cell lines the addition of anti-EGFR therapy reversed oxaliplatin resistance.26 Additionally, a synergistic antitumour effect of combined cetuximab and S-1 was apparent in gastric cancer cell lines overexpressing EGFR.25, 27 In colorectal cancer, somatic mutations in codon 12, 13, or 61 of the KRASoncogene confer resistance to panitumumab therapy.11, 28 MET amplification with or without KRAS mutations might be associated with resistance to cetuximab therapy in gastric cancer cell lines;29 however, no validated predictive biomarkers for this setting exist.

Unfortunately, despite preclinical data suggesting a role for anti-EGFR therapy in the treatment of oesophagogastric adenocarcinoma, the REAL3 trial findings are supported by two other phase 3 trials assessing anti-EGFR therapy in this disease setting. The EXPAND trial15 assessed the addition of cetuximab to a cisplatin-capecitabine doublet in 904 patients with previously untreated adenocarcinoma of the stomach and gastro-oesophageal junction, and did not meet its primary endpoint of improved PFS (HR 1·09, 95% CI 0·92—1·29, p=0·32).15 EXPAND also noted no improvement with the addition of cetuximab in either overall survival (HR 1·00, 95% CI 0·87—1·17, p=0·95) or overall response rate (30% in the experimental group vs 29% for controls). The COG trial30 assessed the anti-EGFR tyrosine-kinase inhibitor gefitinib compared with placebo in the second-line treatment of 450 patients with oesophageal and type I—II gastro-oesophageal junction cancers. This trial also did not meet its primary endpoint, with no improvement in overall survival (HR 0·90, p=0·285). However, improvements in PFS (HR 0·795, p=0·017) and disease control at 8 weeks (25·5% in the experimental group vs 16·0% in controls, p=0·014) were noted, suggesting some activity of gefitinib in a small undefined subset of patients.

Taken together, these relatively consistent findings suggest that the EGFR pathway is unlikely to represent an important therapeutic target in most patients with oesophagogastric cancer (panel). The presented biomarker analyses accompanying the REAL3 trial are restricted by small patient numbers and low rates of tested mutations. However, this work is ongoing in the full trial dataset and these translational analyses represent a unique opportunity to further assess the molecular biology of advanced oesophagogastric adenocarcinoma within a randomised trial setting. Techniques such as gene-expression profiling and next-generation sequencing might help to provide further information regarding the driver genetic events in this complex disease. Furthermore, the evaluation of genetic aberrations in pathways linked to EGFR signalling could still offer the prospect of identification of a low-frequency biomarker that identifies a subpopulation of patients benefiting from anti-EGFR targeted therapy in this setting.

Source: lancet

Panitumumab in Patients with KRAS Wild-Type Colorectal Cancer after Progression on Cetuximab.

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Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type meta-static colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab.

Patients and Methods We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies.

Results We treated twenty patients for a median of two cycles (range 1–4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. Panitumumab was well tolerated. Thirteen patients (65%) had grade 1–2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies.

Conclusions Panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab.

Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. Cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents.

Source:The Oncologist

 

Second-Line Panitumumab for Colorectal Cancer

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Adding panitumumab to chemotherapy improved progression-free survival and response rate, but not overall survival, in patients with KRAS wild-type CRC.

Advances in first- and second-line chemotherapy have improved the rate of overall survival (OS) in patients with metastatic colorectal cancer (CRC). The anti–epidermal growth factor receptor (EGFR) agents cetuximab and panitumumab are effective for treating patients with advanced CRC who have KRAS wild-type tumors, and treatment with cetuximab plus chemotherapy in first- and second-line therapy has been associated with benefits in progression-free survival (PFS) and antitumor response. Moreover, a recent study demonstrated the effectiveness of panitumumab as part of first-line chemotherapy in patients with KRAS wild-type CRC (JW Oncol Hematol Jan 25 2011).

Now, industry-supported investigators report results of the first study to evaluate panitumumab as part of second-line chemotherapy for nearly 1200 patients with metastatic CRC and disease progression despite one prior chemotherapy regimen. Patients were randomized to receive fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without panitumumab (6 mg/kg) every 2 weeks. Of 1083 patients with tissue available for KRAS testing, 55% had KRAS wild-type tumors and 45% had KRAS mutant tumors.

Among KRAS wild-type patients, panitumumab recipients fared significantly better than nonrecipients in terms of PFS (median, 5.9 vs. 3.9 months; hazard ratio, 0.73; P=0.004) and response rate (35% vs. 10%; P<0.001), but not OS (14.5 and 12.5 months). Among patients with KRAS mutant tumors, panitumumab recipients and nonrecipients achieved similar PFS (5.0 and 4.9 months), RR (13% and 14%), or OS (11.8 and 11.1 months).

Comment: Second-line therapy with FOLFIRI plus panitumumab was more effective than FOLFIRI alone in patients with metastatic KRAS wild-type CRC. These findings are consistent with data from similar trials showing that second-line therapy with cetuximab improved PFS and RR, but not OS. Given the lack of an OS benefit in the current study, it is appropriate to attempt second-line chemotherapy alone, without panitumumab, in patients with KRAS wild-type CRC and to consider adding panitumumab if the disease progresses.

— David H. Ilson, MD, PhD

Published in Journal Watch Oncology and Hematology February 1, 2011