Select Excerpts from the Interview

Track 2

DR LOVE: Would you provide an overview of the predictors of response to EGFR tyrosine kinase inhibitors?

DR LYNCH: The field has progressed rapidly in the past 10 to 12 months in terms of what we know about predicting response to EGFR TKIs. We’ve seen a remarkable number of studies, which have been very consistent in demonstrating a particularly dramatic response to erlotinib and gefitinib in patients with mutations in the tyrosine kinase domain of the EGFR gene.

However, when looking at a retrospective subset (Tsao 2005) from the large randomized trial BR-21 from Canada (Shepherd 2005), we are not able to associate patient survival with mutations (1.1). Rather, what appeared to be more important in the BR-21 subset is gene copy number, as measured by FISH, and immunohistochemistry (IHC) of the EGFR protein.

These are very important measures and may reflect tumors that have a certain degree of dependence on the epidermal growth factors.

DR LOVE: Is this information of practical use to an oncologist currently?

DR LYNCH: Right now, it’s a little unclear. When I see a patient with an adenocarcinoma — basically, all patients with nonsquamous cell tumors — I frequently obtain EGFR sequencing up front. If the disease is mutation positive, the patient qualifies for a clinical trial looking at EGFR TKI therapy in the first line.

Track 8

DR LOVE: Right now, when you’re evaluating a patient for adjuvant therapy, do you offer adjuvant erlotinib off trial to a younger patient in his or her fifties who is either a nonsmoker or has the mutation?

DR LYNCH: I don’t, but that’s one of the questions we frequently debate. The reason I don’t offer a TKI off protocol is based on the results of the SWOG S0023 study (Kelly 2005), which randomly assigned patients to gefitinib or placebo after chemoradiation for Stage III lung cancer (1.2). That study showed patients who received adjuvant gefitinib had a worse outcome, not statistically significant but very close to being statistically significant, than patients who received placebo.

DR LOVE: I remember asking you previously what you would do if you were in that situation — a nonsmoker with a mutation in the adjuvant setting. As I recall, you said you’d probably opt for treatment.

DR LYNCH: I said that I would probably choose treatment because I’d be willing to accept that risk for myself. So it is something we need to discuss with patients, to see if they’re willing to accept the risk — which may be an increased risk of death in this setting.

To be quite frank, we’re not going to have this answer for seven to 10 years.

Track 15

DR LOVE: Where are we right now in terms of trials evaluating bevacizumab in the adjuvant setting? Can you speculate whether bevacizumab might be more or less effective in the adjuvant compared to the metastatic setting?

DR LYNCH: We have a trial just starting at Massachusetts General Hospital and at the Dana-Farber Cancer Institute in which we’re treating patients with chemotherapy and bevacizumab in the adjuvant setting.

It’s a pilot study and the design is straightforward: 50 people, Phase II, and just getting off the ground now. We’re looking at the use of bevacizumab/carboplatin/ paclitaxel in the adjuvant setting. Patients must be treated within eight weeks of surgery, they can’t show any evidence of hemoptysis, and they must have T2 tumors or greater. Patients with Stage IA disease are not eligible.

DR LOVE: Do you include patients with squamous cell disease in the trial?

DR LYNCH: In completely resected lung cancer, no squamous cells should remain so there is no theoretical reason that patients should bleed. I don’t think there’s any reason to believe bevacizumab would not be beneficial in that group of patients, so we will be including patients with squamous cell disease in the trial.

Track 20

DR LOVE: Do you use chemotherapy after chemoradiotherapy in patients with Stage IIIB disease? The SWOG regimen utilizing docetaxel maintenance has generated a lot of excitement. Can you talk a little bit about that and discuss the updated data (Gandara 2005) that were presented at ASCO?

DR LYNCH: The SWOG-S9504 data look very encouraging. Etoposide/ platinum was used in a 50-50 combination in which you administer 50 mg/m² of platinum on day one and day eight and 50 mg/m² of etoposide on days one to five. That way, full doses of etoposide/platinum are received in cycle one and cycle two. When you administer that combination with radiation, you have 12 days of overlap. I believe that’s a very good regimen. Cisplatin/etoposide with radiation is followed by three cycles of docetaxel, and I believe this is a very good approach. The SWOG data showed a median survival of 26 months at 32 months follow-up (1.3).

However, I tend to use weekly carboplatin with a taxane for patients with reasonable functional status who either have impaired organ function or marginal performance status, or for people who I don’t think can tolerate cisplatin. Generally, I tend to be a very big believer in the SWOG trial until convinced otherwise.

We’ll have some data coming out from a Hoosier Oncology Group study (LUN01-24; [1.4]) which evaluated etoposide and cisplatin with radiation therapy followed by docetaxel, asking whether the posterior docetaxel is important in that setting.

This will be a very important trial. Some subsets of Karen Kelly’s SWOG- 0023 trial do suggest that the cisplatin/etoposide followed by docetaxel arm appears to be holding up pretty well.

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