Revisit the day in a new archive
On Sept. 24, 2002, the Oncologic Drugs Advisory Committee recommended an accelerated approval for AstraZeneca’s Iressa (gefitinib). The recommendation concluded a meeting where ODAC weighed whether the drug, an EGFR tyrosine kinase inhibitor, could benefit patients with resistant or refractory non-small cell lung cancer as a third-line therapy.
An archive of FDA documentation from this meeting is now available in the Cancer History Project, as part of a series marking the 20th anniversary of the publication of papers on the role of the EGFR mutation in lung cancer.
A story about this meeting appears in this issue.
The main clinical trial under consideration examined two different doses of Iressa in 139 patients—without a control arm—and found only a 10% objective response rate to both doses. About 40% of participants experienced symptom improvement. Another trial backed up those results.
Despite the meager response rate, those who responded to Iressa did so rapidly and robustly. Most of the 22 responders achieved partial response status by week 4, and all of them achieved PR by 16 weeks.
Said ODAC consultant Claudette Varricchio, then of the National Institute of Nursing Research, to AstraZeneca representatives:
It is impressive that when it works, it really works, and when it doesn’t, it doesn’t, and trying to see if we can get our thinking around what is it about those people in which it worked that made them different from the ones where it didn’t.
I guess I am just kind of making a request that you mine your data to see if you can find some kind of profile that would predict in which patients this is likely to work if it goes forward. It seems it is an “all or nothing” almost.
Responded George Blackledge, who was clinical vice president of oncology at AstraZeneca:
We believe it is more than an “all or nothing” because we have 40% of patients who have either partial response or stable disease, and 40% of patients who show these quite striking differences in their Lung Cancer Subscale.
But there is a group of patients who are exquisitely sensitive, I agree. And, there is a further group of patients who gain some benefit, and about 50% of patients who really have no benefit.
That is very similar to what we see with many other non-cytotoxic agents. Those are roughly the data you see with tamoxifen, 10-15% good response, stable disease in about 30%, and progression in the rest. It is actually what you see with gleevec. If you look at GIST tumors, which express C-KIT but do not have mutations, the response rate in those patients is 10%. A further 30% benefit and the rest do not benefit.
Something is starting to come out with non-mutated receptors and these inhibitors of these receptors, and it looks as if it is something like that. No one yet knows why it is.
We have over 100 collaborations with laboratories worldwide looking specifically at trying to identify these, but at the present time I am afraid we can’t give more guidance than a pathological subtype.
Partial responses to Iressa were associated with symptomatic improvement, so AstraZeneca claimed that the 10% response rate should predict clinical benefit.
ODAC agreed in an 11 to 3 vote.
Iressa hit the U.S. market in 2003, but was pulled in 2005 because clinical trials in a general population of patients failed to demonstrate a survival advantage.
A decade later, the drug returned—thanks to the discovery of EGFR mutations.
In 2015, FDA approved Iressa for patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test (The Cancer Letter, Aug. 7, 2015).
The ODAC meeting transcript, presentation slides, and other relevant documents are available on the Cancer History Project:
Iressa: Oncologic Drugs Advisory Committee Meeting Sept. 24, 2002
By FDA Oncology Center of Excellence, June 21, 2024
Included documents:
- ODAC meeting transcript: Full transcript of the Sept. 24, 2002 meeting of the Oncologic Drugs Advisory Committee
- Center for Drug Evaluation and Research approval package: Clinical Pharmacology/Biopharmaceutics Review – Application number 21-399
- Iressa Administrative Documents: NDA Team Leader Review, meeting minutes, memorandums, and other related documents, 2000-2003
- ODAC Meeting Agenda: Final agenda for the Sept. 24, 2002 ODAC meeting
- Questions to the Committee: Questions to ODAC for NDA 21-399 ZD 1839 IRESSA® (gefitinib), AstraZeneca Pharmaceuticals LP
- Slide deck 1: “Introduction and Rationale for Clinical Development.” AstraZeneca deck presented by George Blackledge, MD
- Slide deck 2: “The Need for Third-Line Therapy in Non-Small Cell Lung Cancer.” AstraZeneca deck presented by Frances A. Shepherd, MD
- Slide deck 3: “Clinical Efficacy.” AstraZeneca deck presented by Ronald B. Natale, MD
- Slide deck 4: “Safety Profile.” AstraZeneca deck presented by Alan B. Sandler, MD
- Slide deck 5: “Summary.” AstraZeneca deck presented by George Blackledge, M.D.
- Slide deck 6: FDA Review. Introduction and Regulatory Background: Grant Williams, MD; Review of the Clinical Trials: Martin Cohen, MD; Statistical Analysis: Rajeshwari Sridhara, Ph.D.
- Astrazeneca ODAC briefing document: FDA Advisory Committee Meeting Briefing Document NDA 21-399 for the use of IRESSA for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have previously received platinum-based chemotherapy
- FDA team leader comments: These FDA team leader comments provide a regulatory background for ODAC deliberations on the New Drug Application (NDA) for ZD1839 (IRESSA) for NSCLC.
- FDA Medical Officer Review: Clinical review briefing document for NDA 21-399. Medical reviewer: Martin H. Cohen, MD; Medical Team Leader: Isagani Chico, MD; Grant Williams, MD
- Statistics Addendum A
- Statistics Addendum B
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