None expected that FDA would be gentle on Iressa NDA. However, luck of the clear picture on what is going on is troubling.
After quick reading of the info, it sound to me that:
1. It was mistake to tried Irresa together with Taxotere (as first line), and that Iressa is less effective for Taxoid an-sensitive cancer.
<<Iressa:
Using human hepatic microsomes ZD1839 oxidative metabolism was catalysed almost exclusively by CYP3A4. Thus concomitant administration of inducers and inhibitors of CYP3A4 could potentially alter ZD1839 clearance in man. ZD1839 has no obvious enzyme inducing potential and is considered unlikely to produce clinically significant drug interactions due to induction or inhibition of P450 dependent metabolism of coadministered compounds.
Taxotere:
In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism can be inhibited by CYP3A4 inhibitors, such as ketoconazole, erythromycin, troleandomycin, and nifedipine. Based on in vitro findings, it is likely that CYP3A4 inhibitors and/or substrates may lead to substantial increases in docetaxel blood concentrations. No clinical studies have been performed to evaluate this finding (see PRECAUTIONS). >>
2. They are asking for second-line label, while trials protocol and designee does not provide end-points characteristic for second-line therapy.
<<1.1.1 Proposed Indication
IRESSATM is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have previously received platinum-based chemotherapy.>>
Nonetheless, FDA is considering mainly/only Platin and Tax progressed in their analysis, while taking survival benefit (or luck off) from front line trials as failure (contra-indicatory) results. Contradictory view, at least.
<<FDA agrees with the response rate reported by the sponsor, i.e. 22 partial responses among 216 patients (10.2%, 95% CI 6.5%, 15%). FDA analysis indicated, however, that only 139 of the 216 patients were actually refractory/intolerant to both a platinum drug and to docetaxel. A second concern was that an additional 32 patients were declared to be refractory to therapy within 30 days of starting that therapy. If these individuals are also considered ineligible this would bring the total eligible population to 107 patients. While exclusion of ineligible patients does not appreciably change the overall response rate it does decrease the lower bound of the 95% CI to about 5%.>>
Bottom line, Iressa did provide benefit for Stage IIIb/IY NSCLC, where RR did correlate with overall QOL benefit. However, this is not sufficient for accelerated approval, and FDA will ask for new trials, regardless what will be AC respond to NDA.
Miljenko
PS: This should not effect (for now) OSIP or ABGX (IMCL) candidates, but market act first and think later. <grrr> |
