Dacomitinib may Offer New Treatment Option for Patients with EGFR-Positive Lung Cancer

Attendees during American Society of Clinical Oncology (ASCO) Annual Meeting. Courtesy: ? ASCO/Scott Morgan
Attendees during American Society of Clinical Oncology (ASCO) Annual Meeting. Courtesy: ? ASCO/Scott Morgan

Findings from a phase III clinical trial point to a potential new treatment for patients newly diagnosed with advanced, epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). Compared to the EGFR inhibitor gefitinib (Iressa?; AstraZeneca), one of the standard targeted medicines for this disease, the investigational second-generation EGFR inhibitor dacomitinib (PF-00299804; Pfizer), delayed cancer growth by a median of 5.5 months more.

Dacomitinib is an oral, once-daily, pan-HER inhibitor. It is an irreversible inhibitor of HER-1 (EGFR), HER-2 and HER-4 tyrosine kinases. The drug targets multiple receptors of the HER pathway. In contrast, currently marketed HER-1 (EGFR) inhibitors approved for the treatment of non-small cell lung cancer (NSCLC) only target one receptor in this pathway.[1]

The study, called ARCHER 1050, was funded by Pfizer and SFJ Pharmaceuticals Group and featured at the 53rd annual meeting of the American Society of Clinical Oncology (ASCO) held June 2 – 6, 2017 in Chicago, Ill. [2][3]

Incidence of EGFR-positive NSCLC
Each year, about 140,000 people worldwide (15,000 in the United States alone) are diagnosed with EGFR-positive NSCLC. EGFR-positive cancers have genetic changes that lead to an overactive EGFR protein, which fuels the growth of cancer cells. EGFR tyrosine kinase inhibitors (TKI) are the standard treatment for people with newly diagnosed EGFR-positive NSCLC. This study is the first phase III head-to-head comparison of two EGFR TKIs.

Photo 1.0: Tony Mok, MD, Chinese University of Hong Kong, presenting Abstract LBA9007, “Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): A randomized, open-label phase 3 trial,” at the American Society of Clinical Oncology (ASCO) Annual Meeting.

Treatment paradigm
?We changed the treatment paradigm for EGFR-positive lung cancer a few years ago when targeted therapy replaced chemotherapy,? said lead study author Tony Mok, MD, a professor and chair of the Department of Clinical Oncology at the Chinese University of Hong Kong in Hong Kong, China.

?This study shows that dacomitinib may be an even more effective treatment for these patients. However, patients should be aware of the need to deal with potential side effects when making treatment decisions,? Mok added.

Due to its chemical properties, dacomitinib blocks EGFR more effectively than first-generation inhibitors, such as gefinitib and erlotinib, and this explains its ability to keep tumor growth in check longer. On the other hand, this also leads to stronger suppression of the normal EGFRs in healthy tissues, causing more side effects such as skin rash, acne, and diarrhea.

Study design
In this phase III clinical trial, researchers randomly assigned (1:1) 452 patients newly diagnosed with IIIB or IV, recurrent EGFR-positive NSCLC to receive dacomitinib 45 mg PO QD or gefitinib 250mg PO QD.? The patients, harboring an EGFR- activating mutation (exon 19 del or exon 21 L858R mu +/- exon 20 T790M mu), were enrolled in Asia and Europe. Stratification was by race and EGFR mutation subtype and the baseline characteristics were fairly well balanced between the two arms.

Key Findings
Patients who received dacomitinib had a 41% lower chance of cancer progression or death than those who received gefitinib. The progression-free survival was 14.7 months with dacomitinib, compared to 9.2 months with gefitinib. Longer follow up is needed to assess the median overall survival.

The most common severe (grade 3) side effects of dacomitinib were acne (in 14% of patients) and diarrhea (in 8% of patients). The dose of daconitinib was lowered in about 60% of patients due to side effects. Liver enzyme abnormalities were the most common severe (grade 3) side effect of gefitinib (in 8% of patients).


?Intend to Treat Population (ITT)
Dacomitinib
N=227 Median
(months)
Gefitinib
N=225 Median
(months)
Progression Free Survival (PFS) per independent review (IRC)14.7
[95% CI: 11.1,16.6]
9.2
[95% CI: 9.1,11.0]
Stratified HR = 0.59
[95% CI: 0.47,0.74]
1-sided p-value <0.0001
Progression Free Survival (PFS) per Investigator (INV)16.6
[95% CI: 12.9,18.4]
11.0
[95% CI: 9.4,12.1]
Stratified HR = 0.62
[95% CI: 0.50,0.78]
1-sided p-value <0.0001
Duration of response (DR) per independent review (IRC) in responders?14.8?8.3Stratified HR = 0.40
[95% CI: 0.31,0.53]
1-sided p-value <0.0001

?Dacomitinib is a more potent, second-generation EGFR inhibitor that shares the issue of increased side effects in the skin and gastrointestinal tract, like afatinib (Gilotrif?; Boehringer Ingelheim Pharmaceuticals). In spite of this, the activity seen in this study should allow for consideration of this effective therapy in this patient population,? noted Mok.

Afatinib, another second-generation EGFR inhibitor, is already approved by the U.S. Food and Druf Administration (FDA) as an initial treatment for EGFR-positive NSCLC. Dacomitinib is not yet approved for any indication.

Perspective
?It?s been nearly 15 years since EGFR-targeted therapies were introduced, helping extend survival for thousands of patients in the time since. The second generation of these therapies is more effective, but can also cause greater side effects, so patients and their doctors will need to weigh the risks and benefits,? explained John Heymach, MD, PhD, Professor, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston and an independent ASCO Expert not associated with the study.


Last editorial review: June 6, 2017

Featured Image: Attendees at the American Society of Clinical Oncology (ASCO) Courtesy: ? 2017 ASCO/Scott Morgan. Used with permission. Photo 1.0: Tony Mok, MD, Chinese University of Hong KongCourtesy: ? 2017 ASCO/Scott Morgan. Used with permission.

Copyright ? 2017 Sunvalley Communication, LLC. All rights reserved. Republication or redistribution of Sunvalley Communication content, including by framing or similar means, is expressly prohibited without the prior written consent of Sunvalley Communication. Sunvalley Communication shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Onco?Zine, Oncozine and The Onco?Zine Brief are registered trademarks and trademarks of Sunvalley Communication around the world.