I am back, many reading to do.
Iressa results are big shock and frustration is significant, on my side. The big question is what went wrong and what is (logical, if possible) explanation? Also, how will this new development effect ABGX (primary) and OSIP (my secondary interest).
Several follow up posts here and at Valuation tread. Didn’t found right and reasonable explanation.
Iressa is selective for HER1 (with some anti-angiogenic property), while for cell line that also express HER2 drug is ineffective at lower doses.
ncbi.nlm.nih.gov
ncbi.nlm.nih.gov
While HER2 is not as highly expressed in NSCLC as it is HER1, one can not eliminate possibility that homo-HER1 signaling suppression can be compensated by high HER2/neu level which easily form heterodimer with HER1 (and induce phosphorilation). Also, hetero-tetramer is in play here. Second, it is possible that platinum refractory and progressed metastatic NSCLC is in large part driven by “hot” EGFr, so receptor inhibitor may induce initial regression and partial response, but can not work long term.
Interesting that in Iressa front line NSCLC PIII trials EGFr positive test was not condition for enrollment. So, they were betting of some additional drug activity, not only EGFr signaling disruption. Or that HER2 receptor co-expression was not significantly increased in naive lung cancer and will not alter survival benefit, predicted by drug-combination animal model.
Another possible explanation is that in prolonged cancer therapy initial benefit from EGFr blockade decrease due to receptor mutation (active ATP pocket, single mutation may reduce inhibitor potency).
What this mean for Tarceva???
First, going back to 2000 year, I never excepted de facto PFE decision to give-up Tarceva for free, regardless what were FTC dictated WL merge conditions. WL was doing (at some degree in collaboration with Sugen) its own profile for full HER1-2 combination inhibitor (today CI 1033, an irreversible inhibitor) and I think that PFE was aware of the Iressa profile and limitation.
Iressa and Tarceva are very similar in structure, similar in-vitro and in-vivo activity, similar pharmacokinetic, metabolite rate and half life,…
Next two paragraph indicate similar protocol and PIII programs:
Iressa: <<Phase III trials are currently evaluating ZD1839 in combination with gemcitabine/cisplatin or paclitaxel/carboplatin as first-line treatment of non-small cell lung cancer and an ongoing clinical trial programme is investigating other tumours (i.e., head and neck, prostate, colon and breast) and other combinations.>>
Tarceva: <<All three NSCLC Phase III trials are progressing as planned. Accrual was recently completed for the first of the two front-line combination studies for Tarceva(TM) in non-small cell lung cancer (an approximately 1000 patient Genentech sponsored study combining Tarceva(TM) with carboplatin and Taxol®). Accrual to the other front-line combination study (an approximately 1000 patient Roche sponsored study combining Tarceva(TM) with gemcitabine and cisplatin) is currently on track. The single agent, refractory study (an approximate 330 patient OSI sponsored study in refractory NSCLC patients) is also progressing as planned.>>
Speculative translation suggest that OSIP two PIII front line program have small chance to be better than Iressa data. Third PIII trial, monotherapy for progressive lung cancer, may generate positive data (like Iressa), but overall dug utility will be far from expected.
Bottom line, for time “B” I will stay out of OSIP. Why both compound skipped PII combination trials???
How Iressa results effect ABGX (and IMCL)?
Both antibody are selective only for HER1, with some activity for hetero-tetramer. ABGX reported some additional activity of the antibody when bound to cell surface receptor. Apoptosis. Antibody activity will not be effected by receptor mutation, as well as co-expression of the HER2 receptor. Antibody will not block activated receptor, but will reduce available receptor for activation (dimerization).
While only randomized and controlled trial will be able to answer directly what are options for EGF-ABX, I do believe that antibody (like Herceptin for breast cancer) have better chance to induce response and keep that response for while. Unless we are all completely missing true picture about EGFr and cancer growth, antibody should be additive to chemo agent and bring survival benefit. Time will tell.
Miljenko |
