AstraZeneca's Iressa May Pave Way For EGFR Inhibitors In Adjuvant Lung Cancer
Executive Summary
Study done in China may prompt a change the standard of care in the US to include earlier testing for EGFR mutations after surgery, but is unlikely to change treatment protocols until overall survival data are available.
A Chinese study of AstraZeneca PLC's Iressa in adjuvant (post-surgery) treatment of lung cancer with EGFR mutations may pave the way for earlier use of EGFR inhibitors – including next-generation drugs – internationally, though overall survival data will likely be needed to make the change.
Of six abstracts highlighted as key research in the American Society of Clinical Oncology's May 17 press briefing on this year's annual meeting, to be held June 2-6 in Chicago, only one included a branded drug – a pivotal study done in China on the role of Iressa (gefitinib), which is close to going off patent in seven major global markets.
The press briefing also included two studies analyzing nutrition and colon cancer, a study of adjuvant capecitabine in biliary cancer and two studies about cancer screening.
The Iressa presentation (abstract #8500) is the Phase III CTONG 1104 study that compared oral gefitinib to standard of care chemotherapy (vinorelbine with cisplatin) in 222 patients with stage II/IIIa non-small cell lung cancer with EGFR mutations.
The study was funded by the Guangdong Association of Clinical Trials, with some financial support from AstraZeneca China, and was carried out in Asia. AstraZeneca has been working to build the reach of its branded products in China, which accounts for half of its emerging market sales, including the introduction of its next-generation EGFR inhibitor Tagrisso (osimertinib). (Also see "AstraZeneca Upbeat On China Prospects For New Products" - Scrip, 15 Nov, 2016.)
Tagrisso is now being tested for a role in in adjuvant NSCLC in AstraZeneca's international Phase III ADAURA study, which includes trial sites in China. The study, which will include 700 patients, is due to complete in July 2021.
EGFR mutations are much more common in Asian countries compared to Western nations – about 35% compared to 10%. AstraZeneca has noted that China has the largest population of patients with EGFR mutations in the world.
"Given the high rate of smoking in China, the EGFR mutation-positive NSCLC market is a potentially lucrative opportunity," Datamonitor Healthcare analyst Dustin Phan commented.
The CTONG 1104 study hints of potential for other EGFR inhibitors, including first- and second-generation EGFR inhibitors, in Asia and in the West.
Researchers tested Iressa after surgery for 24 months, compared to chemotherapy (vinorelbine/cisplatin) given every three weeks for three or four cycles, a shorter period because the regimen is not as well-tolerated. Even though the treatment period was shorter for chemotherapy, there was a much higher rate of severe adverse events (48% vs. 12%). Disease-free survival was the primary endpoint.
Patients who received chemotherapy had a recurrence 10 months earlier than the Iressa arm: 18 months vs. 28.7 months. Overall survival data are not mature.
Based on the results, researchers concluded that EGFR testing should be done earlier, in the adjuvant setting, to pick up on patients with mutations.
Asked to comment on implications for US practice during the press briefing, ASCO-president elect and Dana Farber lung specialist Bruce Johnson said that it will be important to see what happens in terms of survival, which takes a long time to assess in the adjuvant setting.
Approved by FDA in 2003, Iressa was the first EGFR inhibitor introduced in the US. It was initially approved for a broad population in third-line NSCLC, but then it was discovered that the drug works only in those with EGFR mutations, so labeling was narrowed. (Also see "AstraZeneca's Iressa Use Narrowed: No New Commercial Patients" - Pink Sheet, 17 Jun, 2005.)
AstraZeneca withdrew the drug from the market in 2012, only to have it reapproved in 2015 for first-line NSCLC, ahead of the introduction of next-generation Tagrisso for EGFR+ lung cancer with EGFR mutations. (Also see "AstraZeneca’s Iressa, Now Resurrected, Faces Daunting U.S. EGFR Market" - Pink Sheet, 20 Jul, 2015.)
Boehringer Ingelheim GMBH's Gilotrif (afatinib) is another new entrant to the market, but Astellas Pharma Inc./Genentech Inc.'s Tarceva (erlotinib) is the dominant EGFR inhibitor in the US.
ASCO Chief Medical Officer Richard Schilsky said that based on the data, US doctors may now want to begin testing lung cancer patients right after surgery to see if they have EGFR mutations, which is not currently the standard of care – testing is usually not done until cancer recurs or becomes metastatic, he said.
In terms of potential for a change in practice in the US based on the Chinese study, Schilsky believes that it is important to wait for overall survival data. But it is also important to note that the trial compared just 12 weeks of chemotherapy to two years of gefitinib.
"It's a big commitment on the part of patients to adhere to two years of continued treatment and, secondly, it should not be lost on all of us that the cost of gefitinib treatment is far greater than the cost of 12 weeks of chemotherapy," Schilsky said.
Once the survival data is known, doctors and patients will need to have discussions about the magnitude of the survival benefit and the burden in terms of time and cost of 12 weeks of chemotherapy vs two years of an oral treatment, which is less toxic but not without toxicity, he said.
"A lot of the ultimate decision-making I think will be highly dependent on whether the treatment actually results in an overall survival advantage," Schilsky concluded.