Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer

Jensen, Lars Henrik; Lindebjerg, Jan; Pløen, John; Hansen, Torben Frøstrup; Jakobsen, Anders

doi:10.1093/annonc/mds008

Cited by 92 publications

(57 citation statements)

References 21 publications

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“…We explored any potential explanation for this survival advantage in IHC patients despite similar PFS. In this subgroup, the median number of cycles was 6 (range, [3][4][5][6][7][8][9][10][11][12] in the P-GEMOX group and 11 (range, 2-12) in the GEMOX group, with more patients in the standard arm completing the preplanned 12-cycle treatment (10 patients in the GEMOX group vs 6 patients in the P-GEMOX group). Moreover, we could not demonstrate any significant difference in the causes of the end of treatment, occurrence of adverse events, second-line treatments, or surgery between the arms (data not shown).…”

Section: Resultsmentioning

confidence: 94%

“…Nonrandomized phase 2 studies have shown an ORR of up to 63% or a median OS of up to 20.3 months. 8,[11][12][13][14][15] However, in 2 randomized phase 2 studies of GEMOX with or without cetuximab, anti-EGFR therapy only marginally improved PFS and ORR, with no impact on OS in both European 16 and Asian populations. 17 Similarly disappointing results were obtained with a different approach to EGFR inhibition.…”

Section: Discussionmentioning

confidence: 99%

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Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Leone

Marino

Cereda

et al. 2015

Cancer

123

101

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BACKGROUND: Biliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression. METHODS: This open-label, randomized phase 2 trial recruited chemotherapy-naive patients with advanced BTC displaying a wild-type (WT) KRAS status. Patients were randomized to gemcitabine (1000 mg/m 2 ) and oxaliplatin (100 mg/m 2 ) with (arm A) or without (arm B) panitumumab (6 mg/kg) for up to 12 cycles. The primary endpoint was progression-free survival (PFS) analyzed in an intention-to-treat fashion. RESULTS: Eighty-nine patients (45 in arm A and 44 in arm B) were enrolled between June 2010 and September 2013. After a median follow-up of 10.1 months, the median PFS was 5.3 months (95% confidence interval, 3.3-7.2 months) in arm A and 4.4 months (95% confidence interval, 2.6-6.2 months) in arm B (P 5.27). No survival differences were observed: the median overall survival was 9.9 months in arm A and 10.2 months in arm B (P 5.42). In a subgroup analysis, no differences in PFS according to the site of the primary tumor were observed; patients with intrahepatic cholangiocarcinoma treated with panitumumab may have had a survival benefit in comparison with the control group (15.1 vs 11.8 months, P 5.13). As for safety, skin toxicity was the main adverse event in arm A (80% of the patients). A higher incidence of diarrhea (55.5% vs 31.8%), mucositis (22.2% vs 13.6%), and constipation (24.4% vs 15.9%) was seen in arm A. CONCLUSIONS: These results confirm the marginal role of anti-EGFR therapy even for WT KRAS-selected BTC. Cancer 2016;122:574-81.

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Section: Resultsmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Leone

Marino

Cereda

et al. 2015

Cancer

123

101

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“…A recent phase II trial stratified BTC patients based on KRAS status, but failed to demonstrate that KRAS status predicted the population most likely to benefit from anti-EGFR therapy (45). Furthermore, two biomarker-driven trials that was restricted to KRAS wild-type patients failed to show a clinically significant improvement in PFS or OS using panitumumab combined with chemotherapy (46,47). These studies call into question the utility of KRAS status as a clinically relevant biomarker predictive of EGFR therapy response in BTC, as opposed to colon cancer.…”

Section: Egfrmentioning

confidence: 99%

Current biologics for treatment of biliary tract cancers

Zhao

Lim

2017

J. Gastrointest. Oncol.

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Biliary tract cancers (BTC) is a group of malignancies that arise from the epithelial cells of the biliary tree. These cancers are typically classified by anatomic site of origin: intrahepatic cholangiocarcinoma (IHCC) and extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC). To date, complete surgical resection remains the mainstay of treatment especially for earlier stage disease. Unfortunately, most patients present with advanced or metastatic disease, when systemic chemotherapy is the only treatment option. Due to the paucity of effective treatments, BTCs have a dismal prognosis. There is a tremendous need to better understand the disease biology, discover new therapies, and improve clinical outcomes for this challenging disease. Next-generation sequencing has produced a more accurate and detailed picture of the molecular signatures in BTCs. The three BTC histologic subtypes are, in fact, quite molecularly distinct.IHCC commonly contain FGFR2 fusions and IDH 1 and 2 mutations, whereas EHCC and GBC tend to carry mutations in EGFR, HER2, and MAPK pathway. In light of this emerging knowledge, clinical trials have become more biomarker-driven, which allows capturing of subsets of patients that are most likely to respond to certain therapies. Many new and promising targeted therapeutics are currently in the pipeline.Here we review the genetic landscape of BTCs while focusing on new molecular targets and targeted therapeutics currently being investigated in biomarker-driven clinical trials.

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“…Sohal et al [6] reported efficacy for the combination of panitumumab, gemcitabine, and irinotecan, with a progressionfree survival (PFS) of 9.7 months, among 35 patients. Optimism for EGFR inhibition in BTC grew when Jensen et al [7] published the first prospective marker-driven trial of panitumumab added to combination chemotherapy in advanced disease. The primary endpoint, PFS at 6 months among 46 patients with wild-type KRAS, was 74 %.…”

Section: Discussionmentioning

confidence: 99%

“…Initial studies of anti-EGFR monoclonal antibodies in combination with chemotherapy for BTC among molecularly unselected populations were promising [5][6][7]. The utility of EGFR pathway manipulation in cholangiocarcinoma has also been observed with the combination of erlotinib and chemotherapy [8].…”

mentioning

confidence: 99%

TACTIC: a multicentre, open-label, single-arm phase II trial of panitumumab, cisplatin, and gemcitabine in biliary tract cancer

Ferraro

Goldstein

O’Connell

et al. 2016

Cancer Chemother Pharmacol

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Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer

Cited by 92 publications

References 21 publications

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Current biologics for treatment of biliary tract cancers

TACTIC: a multicentre, open-label, single-arm phase II trial of panitumumab, cisplatin, and gemcitabine in biliary tract cancer

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