Select Excerpts from the Interview

Track 2-3

DR LOVE: Can you provide an overview of clinical trial data of nanoparticle albumin-bound (nab) paclitaxel in lung cancer?

DR SOCINSKI: One of the mainstays of treatment in not only lung cancer but also breast, ovarian and other cancers has been taxane-based therapy. However, we know that taxanes are relatively insoluble in aqueous solution — they require the use of solvents, of which Cremophor^® is probably the most notable.

The toxicities associated with the taxanes are not only hematologic. More problematic, typically, are the nonhematologic toxicities, including myalgias, arthralgias, neuropathy and hypersensitivity reactions.

Most of these toxicities may not be mediated by the parent taxane compound but by some of the solvents in which they’re dissolved. Recently published evidence suggests that Cremophor has a direct neurotoxic effect.

Nanoparticle paclitaxel is a formulation of paclitaxel suspended in albumin (1.1). These nanoparticles — micelles — are soluble in water; therefore, they don’t require the use of solvents.

They are administered relatively quickly with a very low incidence of hypersensitivity reactions compared to either docetaxel or paclitaxel. We have what appears to be safer and more convenient administration with less toxicity.

Nab paclitaxel received FDA approval because it provided an improved time to progression in breast cancer in a comparative trial versus paclitaxel (Gradishar 2005; [1.2]).

We conducted a Phase I trial that was presented at the 2005 San Antonio Breast Cancer Symposium, combining nab paclitaxel with carboplatin on either an every three-week or a weekly (days one, eight and 15 every 28 days) schedule (Stinchcombe 2005). It appears to be well tolerated and convenient.

DR LOVE: Two of the potential advantages of nab paclitaxel are a shorter infusion time and the lack of premedication. How do those play out in lung cancer?

DR SOCINSKI: My view is that this agent has a bright future. If the breast cancer data were to be projected on other tumors — and it looks as if the nab formulation delivers the active cytotoxic to the tumor more effectively — and those data coupled with convenience, less toxicity and no need for premedication will impact how we prioritize first-line treatment regimens.

Track 14-15

DR LOVE: Can you discuss the tyrosine kinase inhibitors ZD6474 and AZD2171?

DR SOCINSKI: ZD6474 is purported to have anti-VEGF as well as anti-EGFR properties. It’s a small-molecule tyrosine kinase inhibitor, and it appears to inhibit the VEGF receptor at lower concentrations, but it will also inhibit the EGFR at a slightly higher concentration.

AZD2171 is also a VEGF inhibitor. The NCIC is conducting an interesting Phase II/III trial evaluating carboplatin/paclitaxel with or without this agent. They are entering 150 patients in the Phase II trial and evaluating time to progression. If that endpoint is met, the trial will shift into a larger Phase III trial with approximately 600 patients.

DR LOVE: What do we know about the efficacy of these agents?

DR SOCINSKI: Currently we have a little more data with ZD6474 than with AZD2171. A second-line trial is comparing docetaxel as the control arm to docetaxel combined with two different doses of ZD6474, either 100 or 300 milligrams (Heymach 2005; Herbst 2005c; [1.3]).

In the initial data, the progression-free survival curves were dramatically better for the 100- versus the 300-milligram dose combined with docetaxel, and remember, with the lower dose you’re probably getting primarily VEGF inhibition, whereas with the 300-milligram dose, you’re getting some EGFR inhibition.

This trial is reminiscent of the trials in which combining EGFR drugs with chemotherapy didn’t make a difference. No major toxicity issues were associated with the drug, so this is not a result of patients not receiving the therapy. Rather, it suggests that, based on the mechanism of action, we don’t know that anti-EGFR inhibition in combination with chemotherapy is a good thing. After all, the INTACT, TRIBUTE and TALENT trials were all negative in that population (Giaccone 2004; Herbst 2004; Herbst 2005b; Gatzemeier 2004).

However, because the Phase II trial showed an impressive difference in the progression-free survival of patients treated with the 100-milligram dose of ZD6474, I believe the signal is sufficient to go on to Phase III.

Track 16-17

DR LOVE: What are your thoughts on combining erlotinib and bevacizumab to block both EGFR and VEGF?

DR SOCINSKI: We only have one experience thus far and that’s the study reported by MD Anderson and Vanderbilt (Herbst 2005a; [1.4]). They treated 40 patients in the refractory setting and produced impressive outcome data. The response rate was 20 percent and the stable disease rate was 65 percent in a group of relatively refractory patients. The median survival was approximately 12 months.

DR LOVE: Can you comment on what we know about clinical or tissue predictors of response to TKIs?

DR SOCINSKI: In my mind, the data from the BR-21, TALENT, TRIBUTE and other trials are hypothesis generating, but they haven’t changed my practice (Shepherd 2005; Gatzemeier 2004; Herbst 2005b). We don’t have good standardized methodologies to stain a tumor for EGFR; however, they will evolve.

This is reminiscent of the initial HER2 experience with trastuzumab, when investigators attempted to determine how to screen patients for therapy and whether IHC or FISH is better to measure HER2. We’re going through the same process with the targeted agents for non-small cell lung cancer.

We do have a current CALGB trial targeting patients who have never smoked that randomly assigns them to single-agent erlotinib or erlotinib with carboplatin/paclitaxel in the first-line setting (CALGB-30406).

The data from a number of trials now suggest that EGFR-directed therapy is important for never smokers. The trial includes mandatory tissue collection, so we’re studying all the molecular markers, IHC and FISH in a prospective manner.

In practice, if I have a patient with a good performance status who has failed a first-line platinum-based doublet, he or she is going to receive erlotinib and pemetrexed.

The question is, which one comes first? I use clinical parameters, such as smoking status, histology, and sometimes gender and ethnicity, to guide my selection of EGFR-based therapy in the second-line setting, and if the patient isn’t demonstrating clinical benefit within four to six weeks, I switch to the other agent.

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