Adding gefitinib to chemotherapy improves PFS in EGFR-mutant lung cancer
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Gefitinib administered concurrently with carboplatin plus pemetrexed improved PFS compared with gefitinib alone among patients with untreated advanced non-small cell lung cancer with EGFR mutations, according to results of the randomized phase 3 NEJ009 trial published in Journal of Clinical Oncology.
Researchers noted that the combination also had an acceptable toxicity profile; however, the OS benefit they observed requires further validation.
“We wanted to improve treatment for advanced NSCLC with EGFR mutations with acceptable toxicities,” Akira Inoue, MD, PhD, researcher at Tohoku University School of Medicine, told HemOnc Today. “To the best of our knowledge, the OS result of our research [median, 50.9 months] is the best record among previous phase 3 trials regarding lung cancer chemotherapy. Our new regimen is better than osimertinib [Tagrisso, AstraZeneca] as first-line treatment for NSCLC with EGFR mutations.”
The combination of epidermal growth factor receptor tyrosine kinase inhibitors and platinum doublet chemotherapy has demonstrated efficacy in advanced NSCLC with EGFR mutations, but few data exist on the safety and efficacy of the combination compared with an EGFR TKI inhibitor alone.
In the NEJ009 trial, Inoue and colleagues randomly assigned 345 patients with newly diagnosed metastatic, EGFR-mutated NSCLC at 47 institutions in Japan to gefitinib (Iressa, AstraZeneca) with carboplatin plus pemetrexed (n = 172) or gefitinib alone (n = 173). The combination and gefitinib-only groups had similar baseline characteristics, including mean age (64 years vs. 64.8 years), sex (women, 62.8% vs. 67.1%) and smoking status (never-smokers, 56.4% vs. 56.5%).
PFS, PFS2 and OS served as primary endpoints. Researchers defined PFS2 as the period from the date of random assignment to the point at which both platinum-based therapy and gefitinib became ineffective conceptually. For the gefitinib-only group, they defined PFS2 as the period from randomization to progressive disease of the second-line therapy or death, not including the period between first progression and initiation of second-line therapy.
Objective response rate, safety and quality of life served as secondary endpoints.
Results showed median PFS of 20.9 months with the combination compared with 11.2 months with gefitinib alone (HR = 0.49; 95% CI, 0.39-0.62). However, PFS2 did not significantly differ between the two groups (20.9 months vs. 18 months).
At median follow-up of 45 months, median OS for the combination group was 50.9 months vs. 38.8 months with gefitinib alone (HR = 0.72; 95% CI, 0.55-0.95).
Regardless of subgroup, the forest plots of PFS and OS indicate the superiority of the combination compared with getinib alone, according to the researchers.
Researchers observed an ORR of 84% (95% CI, 79-90) with the combination vs. 67% (95% CI, 60-74) with gefitinib alone.
Among the 23.3% of patients in the gefitinib group and 21.8% in the combination group who received osimertinib post-treatment, median OS was 74.4 months vs. not reached. Researchers noted these median survival rates were longer than those observed among patients in each group who did not receive post-treatment osimertinib (29.8 months vs. 43.8 months).
Grade 3 or higher treatment-related adverse events appeared more common in the combination group (65.3% vs. 31%). These included neutropenia (31.2%), anemia (21.2%) and thrombocytopenia (17.1%). However, a greater percentage of patients in the gefitinib group experienced grade 3 or higher liver toxicity (22.2% vs. 12.4%). One treatment-associated death occurred in the combination group. Researchers observed no differences in quality of life.
“Our colleagues are now conducting a new trial of a combination with osimertinib and carboplatin plus pemetrexed for the same patient population,” Inoue told HemOnc Today. – by Jennifer Southall
For more information:
Akira Inoue, MD, PhD, can be reached at Tohoku University School of Medicine, 2-1, Seiryomachi, Aoba-ku, Sendai, NA 980-8575, Japan; email: akira.inoue.b2@tohoku.ac.jp.
Disclosures : The study was supported in part by the Japan Society for Promotion of Science, the Japanese Foundation for the Multidisciplinary Treatment of Cancer and the North-East Japan Study Group. Inoue reports honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb Japan, Chugao Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Kyowa Hakko Kirin, Mundipharma, Nihonkayaku, Novartis, Ono Pharmaceutical, Pfizer and Taiho Pharmaceutical; consultant/advisory roles with AstraZeneca, Boehringer Ingelheim, Eli Lilly Japan and Merck Sharp & Dohme; and research funding to his institution from Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly Japan, Kyowa Hakko Kirin and Shionogi. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Hossein Borghaei, DO, MS
This trial, along with a similar study from India, shows that chemotherapy plus an oral TKI for patients with NSCLC carrying an EGFR mutation is highly effective. All clinical parameters — such as response, PFS and OS — favor the use of this combination. These agents have limited use in the U.S. and most Western countries. The preferred drug in the U.S. for this population is single-agent osimertinib.
The reported survival rate in this study is significantly better than we have seen before. However, this study is strictly among an Asian patient population and does not represent the U.S. patient population — there might be differences in pharmacogenomics in these populations. Osimertinib also has a significant central nervous system control rate, which we typically do not see with the first-generation TKIs or chemotherapy. In countries where osimertinib is not available or is too expensive for broad access, the combination of chemotherapy plus an older TKI makes sense, particularly when the OS results are this good.
We should keep in mind that the best patients are enrolled in trials and, therefore, the real-world survival rate is likely to be lower than what is reported here; however, that also is true for studies involving osimertinib.
I would like to see the results of the trial, mentioned in the report, with osimertinib plus chemotherapy before I change my practice. However, if I see a patient who cannot access osimertinib, I will certainly discuss chemotherapy plus a first-generation TKI as the best treatment option.
Reference:
Noronha V, et al. J Clin Oncol. 2019;doi:10.1200/JCO.19.01154.
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