Pasi A. Jänne, MD, PhD
The FDA recently approved gefitinib (Iressa) as a first-line treatment for patients with metastatic non–small cell lung cancer (NSCLC) whose tumors have EGFR
exon 19 deletions or exon 21 (L858R) substitution mutations.
The TKI was originally approved by the FDA in 2003 for use in patients with advanced NSCLC whose disease had progressed on both platinum-based therapy and docetaxel. However, data from confirmatory trials did not uphold promising early phase data, and gefitinib was subsequently withdrawn from the market.
The new approval was based on data from the phase IV IFUM trial, which showed an objective response rate (ORR) of 50% with gefitinib in EGRF
-mutant NSCLC determined by blinded independent central review (BICR; 95% CI, 0.41-0.59) and 70% (95% CI, 0.61-0.78) as determined by investigators. The median duration of response (DOR) was 6.0 months BICR and 8.3 months by investigator assessment.
Gefitinib’s approval was also supported by data from the open-label IPASS trial, which included 1217 patients with metastatic NSCLC (adenocarcinoma). Among a subset of 186 EGFR
-positive patients, ORR was 67% with gefitinib (DOR, 9.6 months) versus 41% (DOR, 5.5 months) in patients who received carboplatin/paclitaxel. Progression-free survival (PFS) was 10.9 months in the IRESSA group compared with 7.4 months in the chemotherapy cohort (HR, 0.54; 95% CI, 0.38-0.79).
To better understand the impact of gefitinib’s reentry into the US market, OncLive
spoke with Pasi A. Jänne, MD, PhD, director, Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute.OncLive: What key data led to this approval?Dr Jänne
: There were two trials that formed the basis for this approval. One is called the IPASS trial, which was published a couple of years ago. In this trial, patients were selected based on their phenotype or clinical characteristics that were likely to be associated with response to gefitinib. These included individuals who were never-smokers, as well as Asian patients. All patients in this trial had advanced lung cancer and were randomized to receive either gefitinib or chemotherapy.
The trial was subsequently analyzed with respect to the presence or absence of an EGFR
mutation. The EGFR
mutation is a key biomarker for sensitivity to medicines such as gefitinib. The analysis found that patients who had an EGFR
mutation had a greater response, greater duration of response, and a greater quality of life if they received gefitinib compared to chemotherapy. Those who did not have an EGFR
mutation had the opposite response—they did better with chemotherapy than with gefitinib.
The second trial was IFUM, a prospective trial where only patients with EGFR
mutations were treated with gefitinib as their initial treatment. In that trial, patients had a higher response rate and a prolonged PFS when treated with gefitinib.Can you explain the mechanism of action for gefitinib for NSCLC?
Gefitinib is a kinase inhibitor and, in patients who have EGFR
itself is a kinase. It is an engine of sorts for the cancer cell. In the presence of the mutation, the engine is continuously on and it causes the cancers to grow and spread to different places. What gefitinib does is serve as a break in the engine. It turns the engine off. When the engine is turned off, not only does the cancer stop growing, but also the tumor actually shrinks.How common are EGFR mutations in NSCLC?
In the United States, it makes up about 10% to 15% of patients with lung cancer. That may seem like a small amount, but lung cancer is the most common cause of cancer death in patients in the United States and there are over 200,000 patients diagnosed each year. Because of this, 10% to 15% numerically is actually a very large population of patients—more common than ovarian cancer, for example. Looking at this on a broader scale and worldwide, EGFR
mutations are even more common in Asia. Therefore, there are a significant number of patients that will be impacted by this approval. It really gives more choice of treatment for patients.Do you think EGFR mutation testing will become more common based on this approval?
EGFR testing is certainly increasing every year. EGFR mutations are found in the adenocarcinoma subtype of lung cancer. At our own institution, we test everyone for this mutation. With this approval, the importance of testing is even greater. If patients are not getting tested for genetic alterations, they need to ask their doctor to do so.
Is there any potential for gefitinib to be used in combination with other drugs?
Certainly, there are opportunities to explore combinations. I think that we all believe that one treatment is not going to be enough to cure advanced lung cancer and, ultimately, combinations are going to be necessary. With this approval, we now have the opportunity to develop those combinations for this subset of patients.
Immunotherapy is another exciting area of lung cancer where there have been a lot of advances. Figuring out how targeted therapies like gefitinib work in combination with immunotherapy is an important avenue to pursue.
Is there any opportunity to use gefitinib in other settings?
The approval is in the first-line setting. However, I think if a patient received chemotherapy during their first treatment and then during the course of treatment it is determined that the patients had an EGFR mutation, certainly that individual could be a candidate for gefitinib. Sometimes testing does not happen fast enough, but treatment has to begin. In those cases, gefitinib could be appropriate as the first EGFR inhibitor a patient received even if it was not their first treatment.
Are there any patients with EGFR-mutant NSCLC who are not candidates for this treatment?
This treatment is approved for the two most common EGFR mutations, exon 19 deletions and exon 21, which represent 85% of all EGFR mutations. There are some other EGFR mutations, including a rare one called the EGFR exon 20 insertion that, in general, is resistant to all EGFR inhibitors. Therefore, it is important for patients to understand that not only is the testing important but understanding the subtype of the EGFR mutation is, as well.