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Dacomitinib new first-line treatment option for EGFR-positive non-small cell lung cancer
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CHICAGO — Dacomitinib improved OS compared with gefitinib among patients with newly diagnosed, advanced EGFR-positive non-small cell lung cancer, according to updated phase 3 study results from the ARCHER 1050 trial presented at ASCO Annual Meeting.
Final results showed patients treated with dacomitinib (PF-00299804, Pfizer) had an improvement of 5.5 months in median PFS and 7.3 months for median OS. However, there also was an increase in toxicity.
To date, other clinical trials — including the phase 2b LUX-Lung 7 study and FLAURA — that compared EGFR inhibitors with chemotherapy failed to improve OS. Results of LUX-Lung 7 showed a median OS of 27.6 months with afatinib (Gilotrif, Boehringer Ingelheim) compared with 24.3 months with gefitinib (Iressa, AstraZeneca; HR = 0.85; 95% CI, 0.66-1.09). OS results from FLAURA are not yet mature.
“Last year at ASCO, we reported a positive outcome of the improvement in the PFS with a median of 14.7 months vs. 9.2 months. The question remained whether there would there be an OS benefit,” Tony S. Mok, MD, chair of clinical oncology at The Chinese University of Hong Kong, told HemOnc Today. “We were able to find a definite OS benefit with the median of above 34.1 months vs. 27.8 months. So, it is a significant difference, with a P value of 0.044. With that, this is the first study that is able to show a more potent TKI to be better than the standard [in these patients].”
Gefitinib — an EGFR inhibitor — is approved for first-line treatment of patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 substitution mutations.
Dacomitinib — an investigational second-generation pan-human EGFR tyrosine kinase inhibitor — has demonstrated clinical activity for advanced NSCLC.
The FDA granted priority review to dacomitinib in April for the treatment of patients with locally advanced or metastatic NSCLC with EGFR-activating mutations based on findings from the ARCHER 1050 study.
Mok and colleagues randomly assigned 452 patients with advanced EGFR-positive NSCLC to 45 mg dacomitinib (n = 227) or 250 mg gefitinib (n = 225) once daily. Patients did not have prior systemic therapy for NSCLC, had an ECOG performance score of 0 or 1, and had no evidence of central nervous system metastases at baseline.
A majority of patients were Asian in the dacomitinib (n = 170) and gefitinib (n = 176) groups.
The data cutoff for OS analysis was February 17, 2017. Death occurred among 220 patients — 103 in the dacomitinib group and 117 in the gefitinib group.
Median duration of follow-up for OS was 31.1 months.
The median OS was 34.1 months (95% CI, 29.5-37.7) in the dacomitinib group compared with 26.8 months (95% CI, 23.7-32.1) in the gefitinib group, which resulted in an HR of 0.76 (95% CI, 0.58-0.99).
The median OS was 34.1 months (95% CI, 30.1-not reached) among patients with exon 19 deletion in the dacomitinib group compared with not reached (95% CI, 25-not reached) among patients in the gefitinib group.
The median OS was 32.5 months (25.5-not reached) among patients with exon 21 L858R mutation in the dacomitinib group compared with 23.2 months (95% CI, 19-28.6) among patients in the gefitinib group.
Among Asian patients, the median OS was 34.2 months (95% CI, 30.1-not reached) in the dacomitinib group compared with 29.1 months (95% CI, 25.2-not reached) in the gefitinib group (HR = 0.81; 95% CI, 0.59-1.1).
Median PFS reached 14.7 months among patients randomly assigned to dacomitinib compared with 9.2 months among patients assigned gefitinib.
The adverse events observed with dacomitinib appeared consistent with findings from previous trials. The most common adverse events included diarrhea (87%), nail changes (62%), rash/dermatitis acneiform (49%) and mouth sores (44%).
The most common grade 3 adverse events included rash (14%) and diarrhea (8%). Grade 4 adverse events occurred among 2% of dacomitinib-treated patients. Once case each occurred of grade 5 diarrhea and grade 5 liver disease.
Ten percent of patients randomly assigned to dacomitinib discontinued treatment due to adverse events compared with 7% of patients treated with gefitinib.
Toxicity levels were higher than expected, Mok said.
“The dose we chose was a little bit higher than what we should’ve picked, so there could potentially be a bridging study to introduce a lower dose of 30 mg with dose escalation of 45 mg, which may be on the map right now,” Mok said.
One of the differences between the two agents is the toxicity.
“The toxicity of a second-generation agent is typically higher because it is more potent, whereas third-generation agents have less major toxicities. Another difference has to do with brain metastases,” Mok said. “Third-generation agents can penetrate the brain, but in this second-generation study, we excluded these patients. So, if there is a relatively so-called fitter person with mutation and no brain metastases, I think you may consider the second generation,” he said, adding that if a patient fails the second-generation therapy, they may still have an approximate 50% chance of using a third-generation agent subsequently.
“We want more options for patients. Now we have five or six drugs available, so it is a matter of more choice for the patient to try and fit the different needs to maximize survival,” Mok said. “ – by Melinda Stevens
Reference:
Mok T, et al. Abstract 9004. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
Disclosures: Mok reports a leadership role with Sanomics Limited; stock and other ownership interests with Cirina and Sanomics Limited; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer and Roche/Genentech; consultant/advisory roles with ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Cirina, Clovis Oncology, Eli Lilly, geneDecode, Ignyta, Merck Serono, Merck Sharp & Dohme, Novartis, Oncogenex, Pfizer, Roche/Genentech, SFJ Pharmaceuticals Group and Vertex; and research funding to his institution from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Eisai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals Group and Taiho Pharmaceutical. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Joshua M. Bauml, MD
Last year at ASCO, we learned that dacomitinib is associated with an improved PFS over gefitinib. This study now shows that there is a modest improvement in OS. It is relevant because it is the first study comparing TKIs that showed an OS difference. Unfortunately, I do not think it will significantly impact treatment in the United States. First, the toxicity of dacomitinib is substantial. This is a very large difference to osimertinib (Tagrisso, AstraZeneca), which supplanted erlotinib (Tarceva, Genentech)/gefitinib as the preferred TKI based upon the FLAURA study. Osimertinib is very well tolerated.
Most oncologists have replaced gefitinib — the comparator here — with osimertinib. Although some would argue that FLAURA did not show an OS benefit, those data are immature, and I hope we will see OS data soon. Based on the PFS benefit, I suspect an OS benefit will be there. Finally, in the presentation last year, most of the benefit to dacomitinib was seen among patients in Asia. The HR appeared much less favorable for patients in North America.
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