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Gefitinib delays recurrence in some patients with lung cancer
Gefitinib significantly prolonged DFS compared with standard-of-care chemotherapy in patients with EGFR–positive stage II or IIIa non–small cell lung cancer, according to a phase 3 clinical trial scheduled for presentation at the ASCO Annual Meeting.
“Lung resection and chemotherapy is standard of care for stage II or IIIa NSCLC,” Yi-Long Wu, MD, director of Guangdong Lung Cancer Institute at Guangdong General Hospital in Guangzhou, China, told HemOnc Today. “But the long-term survival (40%) is not satisfactory and most patients develop disease recurrence in 2 years. Adjuvant chemotherapy gives patients with lung cancer only 10% to 15% survival benefit and patients experience severe toxicity. We hoped this study could tell us how to get much longer remission time and lower toxicity for these patients.”
Approximately 25% of patients diagnosed with NSCLC are eligible for surgery, of whom about 30% harbor an EGFR mutation and may benefit from adjuvant treatment with EGFR–targeted therapy to reduce recurrence risk.
Two previous trials that assessed adjuvant targeted therapy did not show benefit for NSCLC, in part because they included participants with stages I, II and III disease, Wu said.
“The earlier trials only looked to see if patients showed overexpression or over-activity of EFGR, but not mutations in EGFR,” Wu said in a press release. “Our trial recruited patients who had been confirmed to have activating EGFR mutations, so we believe these reasons account for why other trials showed no benefit of a targeted therapy while ours did.”
Gefitinib (Iressa, AstraZeneca) — initially approved by the FDA in 2003 as a third-line therapy for NSCLC — blocks EGFR signaling and is approved as a first-line therapy for advanced NSCLC with an EGFR mutation.
Researchers randomly assigned 222 patients with EGFR mutations to receive gefitinib daily for 24 months or vinorelbine plus cisplatin chemotherapy every 3 weeks for four cycles. Follow-up for disease recurrence occurred at 3 years.
DFS in the intent-to-treat population served as the primary endpoint.
Patients who received gefitinib demonstrated significantly longer median DFS than those who received chemotherapy (28.7 months vs. 18 months; HR = 0.6; 95% CI, 0.42-0.87), as well as significantly higher rates of 3-year DFS (34% vs. 27%; P = 0.013).
“The patients taking gefitinib lived about 10 months longer without recurrence than patients who received chemotherapy, and patients are able to take [gefitinib] for almost 2 years and tolerate it very well,” Wu told HemOnc Today.
Seventy-six patients (34.2%) died during the trial period — 41 in the gefitinib group and 35 in the chemotherapy group.
Results of a subgroup analysis showed lymph node status (pN1/N2) significantly correlated with DFS in patients treated with gefitinib (P < .05).
Fewer gefitinib-treated patients experienced adverse events (12.3% vs. 48.3%; P < 0.001). The most common serious side effects of gefitinib included elevated liver enzymes. Patients who received chemotherapy experienced vomiting, nausea, low blood counts and anemia.
“Seventy-nine percent of patients took gefitinib for more than 1 year and 70% took it for more than 18 months,” Wu said. “No unexpected toxicities were found.”
Researchers retained a tissue repository from the surgically removed lung tumors and plan to perform a comprehensive biomarker analysis to find other potential biomarkers for gefitinib response or resistance, in addition to EGFR.
“Although there are no final OS data reported, we saw longer survival without disease, fewer toxicities and a higher quality of life using gefitinib instead of chemotherapy in a postsurgery setting,” Wu said. – by Chuck Gormley
Reference:
Wu Y-L, et al. Abstract 8500. Scheduled for presentation at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Disclosure: The Chinese Thoracic Oncology Group and AstraZeneca China funded this study. Johnson reports stock and ownership interest with KEW Group; honoraria from Chugai Pharma and Merck; consultant or advisory roles with Amgen, AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Clovis Oncology, Genentech, GlaxoSmithKline, KEW Group, Eli Lilly, Merck, Novartis, and Transgene; research funding from Novartis; and expert testimony for Genentech. Wu reports consultant or advisory roles with AstraZeneca, Boehringer Ingelheim, Merck and Roche; honoraria from AstraZeneca, Eli Lilly, Pfizer, Pierre Fabre, Roche and Sanofi; and researching funding from Boehringer Ingelheim and Roche.
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The drug gefitinib (Iressa, AstraZeneca) became available in the early part of the 2000s after it was provisionally approved. Its full approval depended on a confirmatory trial that researchers reported as being negative. Because of that, the approval was withdrawn in the middle of the 2000s, and the drug had not been available in the United States until it was approved again for EGFRmutant lung cancer in the middle part of this decade. The drug that has been more widely available in the United States is erlotinib (Tarceva; Genentech, Astellas Oncology). Gefitinib has been widely available both in China, as well as in East Asia.
EGFR mutation is about two or three times more frequent in people from East Asia Korea, Japan and China than in a European-derived population, and that may be one of the reasons why, in a broad population, there is more activity with these agents.
One of the good things about this is that the endpoints are measured in years. In advanced lung cancer, you can measure an endpoint in 6 months to a year. In the adjuvant setting, it is going to take years of follow-up.
The first thing we look for is whether we prolonged PFS, and certainly the HR is encouraging. The part we are ultimately interested in seeing is whether gefitinib actually prolongs survival in a longer follow-up study, which Wus group is planning to do.
We are encouraged by the initial results for PFS, but the curves begin to come together beyond 3 years, so it will be very important to see what happens long term in terms of survival. These data are just a few weeks old and I havent changed my approach yet for patients with EGFRmutant lung cancer, but I will be following this very closely to see what happens with survival.
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Gefitinib (Iressa, AstraZeneca) can prolong survival with less toxicity compared with chemotherapy.
It is now standard of care across the country — and probably the world — to screen patients with advanced metastatic lung cancer for EGFR mutations and give them gefitinib or other similar drugs. If the drug works in subsets of patients with advanced disease — although it is not curing people with advanced disease, it prolongs survival and improves quality of life — can we also back the drugs up into treatment of earlier stages of disease to have a major impact? Can you convert people who have lung cancer surgery that are destined to recur and cure those patients?
This is a step in that direction. Researchers evaluated patients with lung cancer and an EGFR mutation — for whom the standard of care is chemotherapy — and asked: Can we get equivalent or better results with gefitinib in this selected group of patients? According to the preliminary abstract, it appears to be a positive study. We are moving in the right direction to take drugs that work in advanced disease and migrate them earlier to try to increase cures.
The chemotherapy used is a relatively standard regimen of infusions every 3 weeks for four cycles — or 12 weeks of therapy — whereas gefitinib is a daily pill they take for 2 years. In general, these targeted agents have less serious side effects than chemotherapy but, nonetheless, patients still have chronic side effects that can interfere with their quality of life. Although the side effects from gefitinib may not be serious and life-threatening, they can consist of chronic skin rashes and chronic diarrhea, which is a problem for quality of life.
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With this information now available, I suspect many doctors will begin testing lung cancer tumors right after surgery to see if patients have an EGFR mutation. That is not currently standard of care in the United States, where typically the testing does not take place until the cancer recurs or becomes metastatic. Doctors and patients can now know whether treatment with an EGFR inhibitor is even an option.
If it is an option, many factors will likely come into play. Most importantly, we’ll be waiting for the survival data. It’s also important to keep in mind that this randomized trial compared about 12 weeks of chemotherapy vs. 2 years of gefitinib (Iressa, AstraZeneca) therapy. That’s a big commitment on the part of patients to adhere to 2 years of continuous treatment. Secondly, the cost of gefitinib treatment is far greater than the cost of 12 weeks of chemotherapy.
Once the survival data are known, doctors and patients are going to need to have very thoughtful discussions about the magnitude of the survival benefit, the burden on the patient to take either cytotoxic chemotherapy for 12 weeks or 2 years of an oral treatment — which, while it is less toxic, is not without toxicity — and the financial burden that treatment choice will have on the patient. The ultimate decision making will be highly dependent upon whether the treatment results in an OS advantage.