A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma

North Central Cancer Treatment Group Trial N064B (Alliance)

Thorvardur R Halfdanarson, Nathan R. Foster, George P. Kim, Jeffrey P. Meyers, Thomas Christopher Smyrk, Ann E. McCullough, Matthew M. Ames, Jeffrry P. Jaffe, Steven Robert Alberts

Research output: Contribution to journalArticle

Abstract

Lessons Learned: Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy. A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy. The dual EGFR-directed therapy resulted in increased toxicity. Background: Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. Methods: Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than.20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. Results: A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530–1.260; p =.1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555–1.280; p =.4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p =.9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p =.0018). Conclusion: Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.

Original languageEnglish (US)
JournalOncologist
DOIs
StateAccepted/In press - Jan 1 2019

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gemcitabine
Adenocarcinoma
Epidermal Growth Factor Receptor
Neoplasms
Survival
Therapeutics
Disease-Free Survival
Pancreas
panitumumab
Erlotinib Hydrochloride
Confidence Intervals

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma : North Central Cancer Treatment Group Trial N064B (Alliance). / Halfdanarson, Thorvardur R; Foster, Nathan R.; Kim, George P.; Meyers, Jeffrey P.; Smyrk, Thomas Christopher; McCullough, Ann E.; Ames, Matthew M.; Jaffe, Jeffrry P.; Alberts, Steven Robert.

In: Oncologist, 01.01.2019.

Research output: Contribution to journalArticle

Halfdanarson, Thorvardur R ; Foster, Nathan R. ; Kim, George P. ; Meyers, Jeffrey P. ; Smyrk, Thomas Christopher ; McCullough, Ann E. ; Ames, Matthew M. ; Jaffe, Jeffrry P. ; Alberts, Steven Robert. / A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma : North Central Cancer Treatment Group Trial N064B (Alliance). In: Oncologist. 2019.
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title = "A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma: North Central Cancer Treatment Group Trial N064B (Alliance)",
abstract = "Lessons Learned: Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy. A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy. The dual EGFR-directed therapy resulted in increased toxicity. Background: Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. Methods: Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than.20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. Results: A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95{\%} confidence interval [CI], 0.530–1.260; p =.1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95{\%} CI, 0.555–1.280; p =.4190). A partial confirmed response was seen in 8.7{\%} of patients on Arm A and 6.5{\%} on Arm B (p =.9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6{\%} vs. 52.2{\%}; p =.0018). Conclusion: Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.",
author = "Halfdanarson, {Thorvardur R} and Foster, {Nathan R.} and Kim, {George P.} and Meyers, {Jeffrey P.} and Smyrk, {Thomas Christopher} and McCullough, {Ann E.} and Ames, {Matthew M.} and Jaffe, {Jeffrry P.} and Alberts, {Steven Robert}",
year = "2019",
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day = "1",
doi = "10.1634/theoncologist.2018-0878",
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T1 - A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma

T2 - North Central Cancer Treatment Group Trial N064B (Alliance)

AU - Halfdanarson, Thorvardur R

AU - Foster, Nathan R.

AU - Kim, George P.

AU - Meyers, Jeffrey P.

AU - Smyrk, Thomas Christopher

AU - McCullough, Ann E.

AU - Ames, Matthew M.

AU - Jaffe, Jeffrry P.

AU - Alberts, Steven Robert

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Lessons Learned: Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy. A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy. The dual EGFR-directed therapy resulted in increased toxicity. Background: Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. Methods: Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than.20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. Results: A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530–1.260; p =.1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555–1.280; p =.4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p =.9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p =.0018). Conclusion: Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.

AB - Lessons Learned: Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy. A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy. The dual EGFR-directed therapy resulted in increased toxicity. Background: Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. Methods: Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than.20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. Results: A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530–1.260; p =.1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555–1.280; p =.4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p =.9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p =.0018). Conclusion: Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.

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