Biotech Tracker News - Affinitak Down But Not Out
March 17, 2003 Isis (NASDAQ: ISIS) and Eli Lilly’s (NYSE: LLY) Affinitak (Isis-3521, LY900003) failed to significantly improve survival rates in a phase III trial of advanced non-small cell lung cancer (NSCLC) patients treated with carboplatin and paclitaxel. Although the antisense drug’s biological ability to make tumor cells more susceptible to standard chemotherapy (chemosensitization) was not translated into a statistically significant survival advantage (primary endpoint), the data released suggest that Affinitak should still be developed for NSCLC. The extent of continued assessment remains to be seen, but further analysis of existing data could lead Isis and Lilly to abandon development of Affinitak for NSCLC. It is more likely that a longer-term effort will be undertaken to define appropriate patient subgroups and optimal trial design.  Affinitak is an antisense inhibitor of the protein kinase-Ca (PKCa) gene, which plays a central role in the development and proliferation of cancer cells. In this phase III NSCLC trial, 616 chemotherapy-naïve study subjects were randomized to receive either standard carboplatin plus paclitaxel or triple-therapy that included the addition of Affinitak. For the primary survival endpoint, the addition of Affinitak was not significantly advantageous, as it was associated with a 10-month median survival compared to a 9.7-month median survival for standard chemo (p=0.81).  Isis and Lilly have suggested that an unexpectedly prolonged control group median survival may overestimate true standard therapy survival. This could mean that a true difference in survival outcomes does exist even though such a difference was not apparent in the trial (a type II error). Whether the magnitude of this purported underestimation is great enough to merit re-assessing another unselected NSCLC cohort remains to be seen.  More likely, any further study would select subgroups more likely to benefit from Affinitak chemosensitization. Data from preliminary subgroup analyses now need to be more rigorously appraised in order to determine whether (1) benefiting subgroups can clearly be defined and, if so, (2) the magnitudes of therapeutic effect for subgroups is great enough to allocate resources to a prospective study designed to support regulatory submission in NSCLC.  Lilly and Isis have thus far stressed “duration of treatment” as one of the “predefined variables” by which patients may be optimally stratified in efforts to define subgroups most likely to benefit from Affinitak chemosensitization. Duration of treatment was amongst multiple variables used in a stratified (log-rank) statistical analysis suggesting subgroup benefit (p=0.048), and was a single variable defining a statistical trend toward survival benefit (p=0.054) for those able to complete a full course of anti-cancer therapy. For the 256 study subjects completing a full, 6-cycle, course median survival was 17.4 months for those receiving Affinitak chemosensitization versus 14.3 months for recipients of chemotherapy alone. Whether relevant patient characteristics (profiles) can be found that permit a reasonably accurate identification of those most likely to complete 6 cycles remains to be seen. Expect analyses of these issues to be presented at the American Society of Clinical Oncology (ASCO) meetings May 31-June 3, 2003 in Chicago.  Affinitak’s tolerability and adverse effect profile was predictable and essentially reassuring. Randomized, open-label, phase III investigation of Affinitak’s addition to gemcitabine and cisplatin is ongoing in NSCLC as well. In the short term, the success of Genta’s (NASDAQ: GNTA) anti-Bcl2 antisense drug Genasense is likely to be the strongest driver of the antisense sector. Results from three phase III Genasense studies are expected this year.
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