[schoonder]

What might have lead Genentech astray.

Was omission of certain non-HER2+ therapies in their T-DM1 trial design a glaring oversight by Genentech that compelled FDA’s RTF response, or was this a misunderstanding by Genentech attributable to lack of specificity by FDA during preceding trial discussions?

Did FDA’s acceptance of trial requirements that did end up receiving Accelerated Drug Approval mislead Genentech in T-DM1's trial construct?
Case in point a recent accelerated approval ruling re: Tykerb where, according to FDA Tykerb WAS NOT compared to Trastuzumab-containing chemo regimen for treatment of MBC. This compare could be done later, why not allow Genentech to correct their shortcoming in the "compassionate" trial setting?
FDA approves TykerbR for use with letrozole to treat certain postmenopausal women with hormone receptor positive metastatic breast cancer


On January 29, 2010, the U.S. Food and Drug Administration granted accelerated approval to lapatinib tablets (Tykerb®, GlaxoSmithKline) for use in combination with letrozole (Femara®, Novartis Pharmaceuticals Corp.) for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor and for whom hormonal therapy is indicated. Lapatinib, in combination with an aromatase inhibitor, has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer. The approval was based on a clinically meaningful increase in progression-free survival (PFS) observed in a single trial (EGF30008). As a condition of accelerated approval, subsequent randomized trials are required to verify and describe the clinical benefit of lapatinib in patients with metastatic breast cancer who have received prior treatment with trastuzumab.

EGF30008 was multinational, randomized, placebo-controlled trial of lapatinib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive metastatic breast cancer who had not received prior therapy for metastatic disease. Patients were randomly assigned to receive lapatinib (1,500 mg once daily) plus letrozole (2.5 mg once daily) or to placebo plus letrozole (2.5 mg once daily). There were 219 patients (17%) who were HER2-positive, 952 (74%) patients who were HER2-negative, and 115 (9%) patients did not have their HER2-receptor status confirmed.

Accelerated approval was based on the results from the group of postmenopausal women with metastatic breast cancer that overexpressed the HER2 receptor. The primary efficacy endpoint was PFS, defined as the time interval between randomization date and the date of either first documented disease progression or death due to any cause. The lapatinib plus letrozole combination had a median PFS of 35.4 weeks compared to 13.0 weeks for the placebo plus letrozole arm (HR = 0.71, p = 0.019). The overall survival data are not mature at this time.

Safety data was evaluated in 1278 postmenopausal women with hormone receptor-positive metastatic breast cancer. The safety profile of lapatinib in this trial population was consistent with previous safety data. The most common adverse reactions (=10%) in the lapatinib plus letrozole arm were diarrhea, rash, nausea, and fatigue. Elevated liver enzymes and bilirubin were reported in 53% and 22% of the patients receiving lapatinib, respectively. Among 654 patients who received the lapatinib plus letrozole treatment, 26 patients experienced Grade 1 or 2, and 6 patients experienced Grade 3 or 4 decreases in left ventricular ejection fraction.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available on the FDA website.

http://www.asco.org/ASCOv2/Practice+&+Guidelines/Practice+Management+&+Reimbursement/FDA+Drug+Alerts/FDA+approves+TykerbR+for+use+with+letrozole+to+tre at+certain+postmenopausal+women+with+hormone+recep tor+positive+metastatic+breast+cancer
Roche surely isn't shirking their responsibility in completing evaluating T-DM1, presently company is conducting two large, international MBC phase III trials. The issue is that, what appears to be a minor technicality, an inconsistent ruling by FDA, is keeping this drug for at least two years out of hands of critically sick people, of which a good many no longer have viable options for efficacious treatment on hand.