In the Q&A forums recently, members Jianming and Neil introduced us to the novel agent XL647, in clinical trials now, but I figured it was worth me collecting more background and providing a more thorough background. XL647 is an oral small molecular that inhibits multiple tyrosine kinases, receptors on cells that trigger cascades of activity in the cells, thereby leading to tumor development and growth. Felt to be most important among these is EGFR (the target of tarceva and Erbitux, for instance), HER-2/neu (which is very important in breast cancer and may have a role in some lung cancers), and VEGF, which mediates blood supply in normal tissues and also cancers. So here is a figure of the key targets for XL647, sitting in a cell membrane:

The tyrosine kinase portion, which is like an ON/OFF switch for a parade of cellular activities like growth and dividing, is on the inside of the cells.

We have drugs that block each of these targets separately, but that entails giving three different medications. We don’t know yet whether hitting all three targets simultaneously with one drug, a multi-kinase inhibitor, is a better approach.

One other key factor that triggered interest in XL647 emerges from lab work with cancer cells that have a mutation that induces resistance to tarceva, called T790M and found in about half of the cancers that transition from responsive to resistant. This research has shown that XL647 has activity in cells that have this mutation, thereby potentially inducing responses in patients who have become resistant to tarceva. But this is still lab work, not people.

Early work in patients is beginning to emerge, however, led largely by my friend Heather Wakelee at Stanford. She first presented a phase I trial (first experience in humans) with XL647 as a treatment for patients with previously treated advanced solid cancers (things like lung, breast, and colon cancer, and excluding blood-based cancers like leukemia and lymphoma)(abstract here). That first report from 2005 explored different doses and schedules and found no serious side effects; among the 12 patients on the study at that time, they hadn't seen any bona fide responses, but a patient with advanced NSCLC had experienced a minor response and then prolonged stable disease. By the time he presented the 2006 report (abstract here) at the ASCO meeting (numbers updated from the abstract), she and colleagues had accrued 40 patients and established a maximum tolerated dose (by weight, 4.68 mg/kg), later changed to a fixed dose of 350 mg daily for the first 5 days of a 14 day cycle. Above this level, diarrhea was too problematic. One patient with NSCLC had achieved a partial response (more than 50% tumor shrinkage), and a total of 12 others (3 with NSCLC and others with a wide range of cancer types) had demonstrated prolonged stable disease (>3.5 months).

Next was a phase II study that focused specifically on previously untreated patients with NSCLC, rather than heavily treated patients who are often resistant to a wide range of anti-cancer agent. Dr. Naiyer Rizvi from Memorial Sloan Kettering Cancer Center in New York presented some preliminary results with this agent at the World Conference on Lung Cancer in Seoul, Korea this past September (abstract here). This was a single arm trial in which patients with advanced NSCLC received first line XL647, but it included only patients for whom it was suspected that XL647 might be particularly helpful. To be included in the study, patients had to have an EGFR mutation (we don’t routinely test for this, but a few centers do) or meet one of three clinical criteria of being Asian, female, or having a minimal (less than an average of 1 pack per day for 15 years, or quit more than 25 years previously) or no smoking history. Ina ccordance wth Dr. Wakelee's results, XL647 was given on days 1-5 of a 14 day cycle, at a dose of 350 mg per day. Response was measured by scans every 8 weeks. Dr. Rizvi reported that 17 patients (12 women and 5 men), among whom eight were never-smokers, had been enrolled, although 6 were still too early in treatment to evaluate. Of the 11 evaluable, four patients had achieved a stable response and one had stable disease, all continuing on treatment at the time of the report. The other six demonstrated progressive disease. They were still evaluating for EGFR mutations but thus far had not found any among four patients with progression, nor the one with stable disease, nor one with a partial response. We don’t really have much information on side effects except that only 4 cases of serious side effects had been noted, three felt unrelated to treatment and the other a pneumonia that was felt possibly related to XL647.

Obviously, there’s very little we can say from these preliminary results from just 11 patients, except that it has shown activity, but the rate of initial progression is actually higher than I’d expect from just giving chemo in the first line setting.

But we'll be learning more about XL647, and sooner than expected. According to a press release this week, the company completed enrollment on a trial tat had just opened in June for patients who had previously responded on an EGFR inhibitor like tarceva or iressa. This was much earlier to complete enrollment than expected, and because of that, by the ASCO meeting in early June 2008 we should learn more about its activity and whether it can reverse acquired resistance to iressa or tarceva. More news then.