NEW YORK (GenomeWeb) – With the US Food and Drug Administration's approval for AstraZeneca's Iressa (gefitinib), metastatic non-small cell lung cancer patients whose tumors have EGFR mutations now have three personalized treatment options.
Importantly for the drug giant, which has been out of the US lung cancer market for a decade, the approval also may serve as a launch pad for it to re-establish its presence with next generation and combination products.
The FDA approval for Iressa — as a first-line option for metastatic NSCLC patients with exon 19 deletions or exon 21 L858R substitutions in the EGFR gene — comes after the agency restricted the marketing of the drug in 2005 to only patients already benefiting from treatment, based on lackluster study results. In the intervening years, Genentech nabbed the first FDA approval for Tarceva (erlotinib) in the EGFR mutation-positive NSCLC population in May 2013, followed by Boehringer Ingelheim's Gilotrif (afatinib) a few months later.
Since 10 percent of Caucasians and 40 percent of Asians with NSCLC have EGFR mutations, the FDA approved Iressa alongside a companion diagnostic — Qiagen's Therascreen EGFR RGQ PCR Kit — for identifying lung cancer patients most likely to respond. The FDA similarly approved Roche's Cobas EGFR Mutation test as a companion diagnostic for Tarceva, and Qiagen's Therascreen EGFR RGQ PCR Kit alongside Gilotrif. An FDA spokesperson told GenomeWeb that Qiagen submitted a supplementary premarket application for its kit, enabling it to be indicated for use in the context of Iressa.
The latest approval was based on a single-arm study, in which around 100 NSCLC patients with EGFR mutations received Iressa, and the drug shrank tumors in half the patients for an average of six months. The response rates were similar in patients who specifically had exon 19 deletions or exon 21 L858R substitutions.
AstraZeneca also submitted retrospective analysis of more than 180 patients with EGFR mutation-positive metastatic NSCLC who were randomized to receive Iressa or carboplatin/cisplatin. "The results from this subgroup suggested an improvement in progression-free survival with Iressa compared to carboplatin/paclitaxel," the agency said in a statement announcing the approval without providing specific data.
A 10-year comeback?
The FDA had granted accelerated approval to Iressa in 2003 for the treatment of patients with advanced NSCLC after they progressed on double platinum chemotherapy and docetaxel. The approval was based on data showing that the drug shrank tumors in 10 percent of NSCLC patients who had received standard treatments. Subsequently, after a confirmatory study failed to show that Iressa-treated patients lived longer compared to placebo, the FDA in 2005 restricted the drug's indication to only those who had received it and were deriving a benefit, barring the firm from selling Iressa to any new patients. The company at that time also withdrew its European marketing application for the drug.
In the coming years, the scientific understanding around the role of EGFR mutations in lung cancer grew, and FDA clarified its regulatory policies for analyzing predictive biomarkers and developing companion diagnostics as part of drug development programs. But there were several years of uncertainty for the industry that likely contributed to AstraZeneca's decision to launch Iressa in Europe for patients with EGFR mutations in Europe in 2009, but completely pull its accelerated approval application in the US in 2011.
In the early 2000s, Lecia Sequist at Massachusetts General Hospital led the study exploring how lung cancer patients with EGFR mutations responded to Iressa. "For the last 10 years it has been widely used around the world and now it is back in the US," Sequist told GenomeWeb. In her view, the drug's approval yesterday adds to oncologists' armamentarium, and that's a good thing for patients.
However, Sequist noted that oncologists currently don't have data from head-to-head trials to discern a significant difference in efficacy between three options for EGFR-mutated NSCLC: Tarceva, Gilotrif, and Iressa. Several studies should provide more guidance, such as LUX-Lung 7, in which Boehringer Ingelheim is comparing Gilotrif against Iressa. There are also a number of trials by Chinese researchers comparing Tarceva and Iressa in the EGFR-mutated lung cancer population. "When the results [of these trials] mature in the next year or so we will have much more information," Sequist said.
Absent a head-to-head comparison of these agents on efficacy, oncologists may choose an EGFR inhibitor based on its safety profile. "We know [Iressa] is very effective for EGFR mutant patients and it is well tolerated," Sequist said. For example, 96 percent of patients receiving Gilotrif in a clinical trial experienced diarrhea, and 15 percent had severe cases. The rate of diarrhea in a Tarceva trial was 62 percent with around 5 percent of severe cases. Both drugs caused severe skin rashes in around 15 percent of study subjects.
Iressa also causes rash and diarrhea in around 20 percent of patients, according to AstraZeneca. According to one study cited in Iressa's label, 3 percent and 2 percent of patients experienced severe diarrhea and skin reactions, respectively. The drug does carry warnings for less common but serious side effects, such as interstitial lung disease, liver damage, gastrointestinal perforation, and eye disorders.
Price might be another competitive point. Genentech sells Tarceva at the monthly wholesale cost of $5,800, which amounts to nearly $70,000 for one year. Boehringer, meanwhile, has decided to sell Gilotrif just below that for $5,500 per month, according to reports. AstraZeneca did not respond to questions for this article ahead of press time
For the time being, Genentech's Tarceva is the global leader. With several indications in lung cancer and one in pancreatic cancer, Genentech reported 2014 global sales of 1.3 billion Swiss Francs ($1.4 billion), marking a 1 percent dip in sales from 2013 that the firm attributed to competition. Iressa, marketed as a lung cancer treatment in 90 countries (not including the US), last year netted $623 million for AstraZeneca. Boehringer's newcomer Gilotrif, only approved for metastatic NSCLC patients with EGFR mutations, competes with Tarceva and now Iressa, but the firm didn't disclose Tarceva sales in its 2014 annual report.
The FDA approval for Iressa comes as the drug's US patent is approaching expiration in 2017. However, in approving the drug, the FDA pointed out that the marketing approval is for a different patient population that in 2003. Moreover, as a drug for treating a rare molecular subtype of NSCLC, the FDA granted Iressa orphan designation, which generally comes with seven years of data exclusivity.
Meanwhile, in Europe, the market for Iressa is a more mature than in the US, and the less challenging regulatory environment for diagnostics has enabled a variety of companion testing options. AstraZeneca and Qiagen have developed a circulating tumor DNA companion test for Iressa, and Qiagen has the CE-IVD mark for the EGFR RGQ Plasma PCR kit.
In the Iressa Follow-Up Measure (IFUM) study — data from which supported Iressa's European and US approval in the EGFR mutation-positive NSCLC population — researchers tested the reliability for the ctDNA test and reported 94.3 percent concordance rate between tissue and plasma testing. The sensitivity of the ctDNA testing method was 65.7 percent and specificity was 99.8 percent.
Industry observers are hopeful that the next advance in the companion testing space will be in the realm of liquid biopsies for cancer indications where tissue resection is invasive and samples are small. "Qiagen is in discussions with pharmaceutical partners around how to bring blood-based companion diagnostics to the FDA," a spokesperson told GenomeWeb without elaborating. The firm is working with Tokai to measure R-V7 expression in castration-resistant prostate cancer patients' circulating tumor cells, for example.
The tissue problem is particularly acute in lung cancer. Approximately 25 percent of advanced NSCLC patients lack sufficient samples for testing to guide treatment decisions, and so drugmakers are assessing a variety of blood-based testing options. Clovis Oncology recently said it is comparing the performance of Sysmex Inostics' BEAMing assay and Qiagen's TheraScreen EGFR PCR test to identify best responders to its third-generation EGFR inhibitor rociletinib.
As for AstraZeneca, Iressa is probably only the start of its offerings in the US personalized lung cancer space. According to industry observers, entering the personalized lung cancer market with Iressa is a way for AstraZeneca to set up the necessary commercialization infrastructure for new products, like its next-generation EGFR inhibitor AZD9291, which FDA has granted breakthrough therapy status.
The drugmaker is studying AZD9291 in advanced NSCLC patients who have EGFR mutations, as well as T790M resistance mutations. At a European medical conference earlier this year, AstraZeneca reported that in an ongoing Phase I/II trial involving around 280 patients treated with AZD9291, median progression-free survival was 13.5 months, the response rate was 54 percent, and the median duration of response was more than a year. AstraZeneca is also studying Iressa in combination with its anti-PD-L1 immunotherapy MEDI4736.