In the JournalsPerspective

Gefitinib shows activity in advanced esophageal cancer subgroup

The evaluation of epidermal growth factor receptor copy number gain identified a subgroup of patients with esophageal cancer who benefitted from second-line gefitinib, according to a prespecified, blinded molecular analysis of the Cancer Esophagus Gefitinib trial.

In that trial, researchers randomly assigned patients with chemotherapy-resistant esophageal cancer to receive gefitinib (Iressa, AstraZeneca; n = 450) — an EGFR tyrosine kinase inhibitor — or placebo as second-line therapy. A minority subset of patients who received gefitinib demonstrated rapid and durable responses.

Russell D. Petty, MBChB, PhD, professor of medical oncology at the University of Dundee School of Medicine in Scotland, and colleagues hypothesized that genetic alteration of the EGFR pathway would identify patients who would benefit from gefitinib.

“A variety of different EGFR signaling abnormalities have been described in esophageal cancer, including copy number gain of EGFR,” Petty and colleagues wrote. “Study results suggest that chromosomal instability is an early and frequent feature of esophageal cancer pathogenesis, and somatic copy number alterations occur frequently in esophageal adenocarcinoma and squamous cell carcinoma.”

The researchers analyzed biomarker data from patients’ tumors to evaluate EGFR copy number gain by fluorescent in situ hybridization (FISH; n = 292) and EGFR, KRAS, BRAF and PIK3CA mutation status (n = 326).

“Identification of a predictive biomarker for patients who receive benefit from gefitinib would enable a more accurate selection of patients for treatments and prevent futile treatment in those patients who are unlikely to benefit,” Petty and colleagues wrote.

Fifty-nine patients with EGFR FISH–positive tumors (high polysomy, 13%; amplification, 7.2%) who received gefitinib demonstrated superior disease control rate (37% vs. 14%), PFS (HR = 0.55; 95% CI, 0.32-0.95) and OS (HR = 0.59; 95% CI, 0.35-1) compared with the placebo arm.

Performance status, prior treatment, BMI, histology, disease site, age and sex did not appear associated with PFS or OS in EGFR FISH–positive tumors, according to a multivariate Cox proportional hazards analysis.

A post hoc analysis suggested that the patients with EGFR amplification had greater benefit with gefitinib than those with high polysomy (HR for death = 0.21; 95% CI, 0.07-0.64).

Patients with EGFR FISH–negative tumors who received gefitinib also demonstrated superior disease control rates (25% vs. 14%) compared with the placebo arm. However, PFS (HR = 0.87; 95% CI, 0.66-1.12) and OS (HR = 0.9; 95% CI, 0.69-1.18) did not differ among those treated with gefitinib or placebo.

Patients did not demonstrate a difference in disease control rate and survival regarding EGFR, KRAS, BRAF and PIK3CA mutations, or for any mutation vs. none.

EGFR FISH appears to predict a benefit from gefitinib in patients with esophageal cancer whose disease has progressed after previous chemotherapy,” Petty and colleagues wrote. “The role of gefitinib and other anti-EGFR therapies should be explored in prospective clinical trials in different settings in EGFR FISH–positive esophageal cancer, particularly in EGFR–amplified tumors, in which the impact of these agents is likely to be greatest.” – by Kristie L. Kahl

Disclosure: Petty reports honoraria from Eli Lilly and Pfizer; consultant and advisory fees from Bristol-Myers Squibb UK and Eli Lilly; research funding from AstraZeneca, Boston Biomedical, Eli Lilly, Janssen and Merck KGaA; travel accommodations from Bristol-Myers Squibb UK, Eli Lilly and Merck KGaA; and a speaker role with Pfizer. Please see the full study for a list of all other researchers’ relevant financial disclosures.

The evaluation of epidermal growth factor receptor copy number gain identified a subgroup of patients with esophageal cancer who benefitted from second-line gefitinib, according to a prespecified, blinded molecular analysis of the Cancer Esophagus Gefitinib trial.

In that trial, researchers randomly assigned patients with chemotherapy-resistant esophageal cancer to receive gefitinib (Iressa, AstraZeneca; n = 450) — an EGFR tyrosine kinase inhibitor — or placebo as second-line therapy. A minority subset of patients who received gefitinib demonstrated rapid and durable responses.

Russell D. Petty, MBChB, PhD, professor of medical oncology at the University of Dundee School of Medicine in Scotland, and colleagues hypothesized that genetic alteration of the EGFR pathway would identify patients who would benefit from gefitinib.

“A variety of different EGFR signaling abnormalities have been described in esophageal cancer, including copy number gain of EGFR,” Petty and colleagues wrote. “Study results suggest that chromosomal instability is an early and frequent feature of esophageal cancer pathogenesis, and somatic copy number alterations occur frequently in esophageal adenocarcinoma and squamous cell carcinoma.”

The researchers analyzed biomarker data from patients’ tumors to evaluate EGFR copy number gain by fluorescent in situ hybridization (FISH; n = 292) and EGFR, KRAS, BRAF and PIK3CA mutation status (n = 326).

“Identification of a predictive biomarker for patients who receive benefit from gefitinib would enable a more accurate selection of patients for treatments and prevent futile treatment in those patients who are unlikely to benefit,” Petty and colleagues wrote.

Fifty-nine patients with EGFR FISH–positive tumors (high polysomy, 13%; amplification, 7.2%) who received gefitinib demonstrated superior disease control rate (37% vs. 14%), PFS (HR = 0.55; 95% CI, 0.32-0.95) and OS (HR = 0.59; 95% CI, 0.35-1) compared with the placebo arm.

Performance status, prior treatment, BMI, histology, disease site, age and sex did not appear associated with PFS or OS in EGFR FISH–positive tumors, according to a multivariate Cox proportional hazards analysis.

A post hoc analysis suggested that the patients with EGFR amplification had greater benefit with gefitinib than those with high polysomy (HR for death = 0.21; 95% CI, 0.07-0.64).

Patients with EGFR FISH–negative tumors who received gefitinib also demonstrated superior disease control rates (25% vs. 14%) compared with the placebo arm. However, PFS (HR = 0.87; 95% CI, 0.66-1.12) and OS (HR = 0.9; 95% CI, 0.69-1.18) did not differ among those treated with gefitinib or placebo.

Patients did not demonstrate a difference in disease control rate and survival regarding EGFR, KRAS, BRAF and PIK3CA mutations, or for any mutation vs. none.

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EGFR FISH appears to predict a benefit from gefitinib in patients with esophageal cancer whose disease has progressed after previous chemotherapy,” Petty and colleagues wrote. “The role of gefitinib and other anti-EGFR therapies should be explored in prospective clinical trials in different settings in EGFR FISH–positive esophageal cancer, particularly in EGFR–amplified tumors, in which the impact of these agents is likely to be greatest.” – by Kristie L. Kahl

Disclosure: Petty reports honoraria from Eli Lilly and Pfizer; consultant and advisory fees from Bristol-Myers Squibb UK and Eli Lilly; research funding from AstraZeneca, Boston Biomedical, Eli Lilly, Janssen and Merck KGaA; travel accommodations from Bristol-Myers Squibb UK, Eli Lilly and Merck KGaA; and a speaker role with Pfizer. Please see the full study for a list of all other researchers’ relevant financial disclosures.

    Perspective

    Author Name

    Slow but steady progress has been made in the treatment of advanced esophagogastric cancer. The increased use of colorectal cancer chemotherapy schedules — such as FOLFOX, capecitabine-oxaliplatin, and FOLFIRI — has resulted in less therapy-related toxicity than 4- to 5-day infusions of 5-FU with high-dose cisplatin. With the advent of ramucirumab (Cyramza, Eli Lilly) enhancing the effectiveness of second-line paclitaxel, there also is diminished interest in using a taxane in first-line therapy. Two areas of targeted therapy development have yielded positive results in phase 3 trials: HER-2 with trastuzumab (Herceptin, Genentech) and VEGF with ramucirumab.

    Agents targeting PDL-1 have now also yielded positive results. Nivolumab (Opdivo, Bristol-Myers Squibb) improved PFS and OS, and induced antitumor responses, in refractory gastric cancer compared with supportive care alone. In a large phase 2 expansion cohort, pembrolizumab (Keytruda, Merck) achieved meaningful responses among patients with refractory disease, particularly in PD-L1-positive cancers. 

    Emerging genomic profiling data indicate discrete genomic subsets of esophagogastric cancer, and gene amplification of HER-2, EGFR, MET and FGFR in small but significant subsets of patients. However, beyond HER-2 and VEGF, phase 3 trials adding EGFR- or MET-targeted agents to chemotherapy have failed to improved outcomes, even in trials of MET inhibitors that selected patients for MET overexpression by immunohistochemistry.

    It is with great interest, then, that Petty and colleagues report biomarker analysis data from the U.K. phase 3 COG trial. The trial failed to show improved OS with gefitinib. In evaluation of tissue from 340 patients, increased EGFR copy number as assessed by FISH — observed in 20% of patients — correlated with improved survival and response to treatment with gefitinib. FISH-positive patients showed improved PFS and OS, which translated into 6-month (38% vs. 14%) and 12-month (13% vs. 0%) survival improvements. The benefit for PFS held up in a multivariate analysis, which trended significant for OS.  

    A greater proportion of FISH-positive vs. -negative patients achieved disease control (27% vs. 14%), and three partial response (10%) occurred among the FISH-positive group.

    In particular, actual gene amplification of EGFR — observed in 7% of patients — had the strongest correlation with OS benefit from treatment with gefitinib. These data are hypothesis generating and indicate a potential biomarker for the use of EGFR-targeted agents in metastatic esophagogastric cancer. 

    The benefits for gefitinib — as is the case in any late-line trial in refractory disease — resulted in relatively high HRs given the poor outcome in placebo-treated patients. Somewhat marginal benefits for therapy, therefore, appear significant, but may not always be clinically meaningful with absolute difference in outcome measured in weeks to a few months. The use of FISH and gene amplification testing for EGFR needs to be validated in other trial series. Anxiously awaited are biomarker data from three randomized trials evaluating the addition of either cetuximab (Erbitux, Eli Lilly) or panitumumab (Vectibix, Amgen) to first-line chemotherapy in metastatic esophagogastric cancer. These include the CALGB trial 80403, the REAL-2 trial and the EXPAND trial, which collectively treated over 2,000 patients. 

    References:

    Bang Y-J, et al. Lancet. 2010;doi:10.1016/S0140-6736(10)61121-X.

    Doi T, et al J Clin Oncol. 2016;doi:10.1200/jco.2016.34.4_suppl.7.

    Kudo T, et al. Lancet Oncol. 2017;doi:10.1016/S1470-2045(17)30181-X.

    Wilke H, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70420-6.

    David H. Ilson, MD, PhD

    Memorial Sloan Kettering Cancer Center

    HemOnc Today Editorial Board Member

    Disclosure: Ilson reports no relevant financial disclosures.