Select Excerpts from the Interview

Track 1

DR LOVE: What common questions about adjuvant therapy are you asked by community-based oncologists?

DR SOCINSKI: The question I hear most frequently is regarding the approach to node-negative disease. Controversy has existed since ASCO 2006 about the role of chemotherapy for patients with Stage IB disease. These patients were included in the positive adjuvant trials, although the subset analyses were negative (Douillard 2006; Winton 2005).

I don’t put much weight on the subset analyses not powered to show a difference. So if the trial had the eligibility criteria of Stage IB to IIIA disease and it was positive, then to me the patients with Stage IB to IIIA disease are eligible for that treatment.

I believe we will ultimately prove that the potential benefit of adjuvant chemotherapy for patients with Stage IB disease is as good as it is for patients with Stage II or Stage III disease in terms of the relative risk reduction. I’m banking on the precedent in other solid tumors that we’ll see the same results.

So if you have a patient with a Stage IB tumor who is a good candidate for adjuvant therapy, it’s reasonable to offer treatment. The next Intergroup trial (E1505) will include patients with Stage IB tumors larger than four centimeters.

Tracks 10-11

DR LOVE: What is your treatment approach for patients with Stage IV NSCLC?

DR SOCINSKI: I view patients with Stage IV disease and a good performance status as belonging to one of three major groups: patients who should receive bevacizumab, patients who shouldn’t receive bevacizumab and “never smokers.”

It’s interesting to talk to physicians across the United States about the percentage of patients in their practices they consider eligible to receive bevacizumab. A wide spectrum is evident, ranging from around 20 percent to about 60 to 70 percent.

DR LOVE: When you start a patient on chemotherapy with bevacizumab, how long do you continue the bevacizumab?

DR SOCINSKI: In ECOG-E4599, patients were supposed to continue bevacizumab until disease progression (Sandler 2006). One of the philosophical debates we often have is whether the benefit of bevacizumab or anti-angiogenic drugs is maximized in the presence of chemotherapy, and do you obtain much benefit after the chemotherapy is stopped?

We’ve had trial designs in which bevacizumab was stopped when the chemotherapy was ended. I don’t believe we have an answer.

I believe that if you conduct a Phase III trial and it’s positive, then when you translate that into practice, you should follow the approach used in the Phase III trial. So I have continued my patients on bevacizumab after I’ve stopped the chemotherapy, which is typically carboplatin/paclitaxel.

Track 12

DR LOVE: What are your thoughts about the AVAiL trial evaluating cisplatin/gemcitabine with or without bevacizumab at two different dose levels?

DR SOCINSKI: As a purist, I’d point out that the AVAiL trial wasn’t designed to address the dose question.

The way I interpret AVAiL is that it’s a second positive trial evaluating the use of bevacizumab in combination with chemotherapy — in this case, cisplatin/ gemcitabine. The regimen appears to be safe, and both the 7.5-mg/kg and the 15-mg/kg doses improved the primary endpoint of progression-free survival (Manegold 2007). No survival data were presented.

The 7.5-mg/kg dose did not appear to be less toxic, and I have continued to use 15 mg/kg, based on the survival results from ECOG-E4599 (Sandler 2006). I would bet that at least by ASCO 2008, we will see some survival data from the AVAiL trial, and perhaps that will change our minds about the dosing. For right now, in the absence of survival data in that trial, I’ve continued administering the 15-mg/kg dose.

Track 14

DR LOVE: What are your thoughts about the combination of bevacizumab and erlotinib?

DR SOCINSKI: The attractiveness of combining erlotinib and bevacizumab is that they target two new and validated pathways. Each of them by itself has been shown to improve survival. This also gets away from some of the traditional toxicities we see with chemotherapy, and I believe it makes biologic sense.

The initial data from MD Anderson and Vanderbilt were encouraging (Herbst 2005a). Those data were moved into the randomized Phase II trial, which suggested that bevacizumab in combination with either chemotherapy or erlotinib was better than chemotherapy alone.

They also suggested that the combination of erlotinib and bevacizumab appeared to be as good and had less toxicity compared to chemotherapy with bevacizumab (Fehrenbacher 2006; [2.1]).

I believe this opens up the possibility that some patients may be better served with a noncytotoxic approach by combining these novel targeted agents. We do have some ongoing Phase III trials that will answer this question about that combination.

We also have to remember that we may be able to identify with various biomarkers the patients who — at least from the erlotinib point of view — may be the best candidates for that approach.

Tracks 16

DR LOVE: What questions are you asked by practicing oncologists about metastatic disease?

DR SOCINSKI: What to do for never smokers. The never smokers represent approximately 10 percent of the population. In my experience, if you use the cutoff of 10 to 15 pack years, the oligosmokers comprise approximately another 10 percent.

So one in five patients with lung cancer fall into this category. That’s not insignificant when you consider the number of patients with lung cancer. The one observation I am convinced of in that population is that anti-EGFR therapy seems to be important.

The question I struggle with regarding the never smokers is that many of them are eligible for bevacizumab. What do you do in that setting? Are they candidates for erlotinib or bevacizumab? What’s the role of chemotherapy?

One option is to treat these patients with chemotherapy and bevacizumab and then, as we continue the bevacizumab, perhaps add erlotinib. We have a lot of safety information, and I don’t believe we’re going to harm patients with that approach.

If patients are not bevacizumab candidates — let’s say they have brain metastases — then the question is, should we use chemotherapy followed immediately by a maintenance strategy with erlotinib or chemotherapy with erlotinib or erlotinib alone?

In CALGB, we currently have a trial (CALGB-30406; [2.2]) that randomly assigns these patients to erlotinib alone versus carboplatin/paclitaxel with erlotinib. It is exploring two of those three possibilities.

You might argue that we should have used four cycles of chemotherapy followed immediately by erlotinib or chemotherapy alone as a control arm, but there’s only so much you can do in a randomized Phase II trial to sort out these issues.

Track 17

DR LOVE: What are your thoughts about nanoparticle albumin-bound (nab) paclitaxel?

DR SOCINSKI: The breast cancer data have encouraged me to be optimistic about nab paclitaxel. It is less toxic and an easier drug to administer in terms of infusion times compared to Cremophor^®-based paclitaxel. That in itself is an advantage, and it may have greater antitumor activity compared to the parent compound or to other taxanes.

The data in lung cancer thus far are limited to Phase II trials (Reynolds 2007; Hawkins 2007), most of which are single-arm and not comparative trials. A plan is in place for a large Phase III trial comparing carboplatin/paclitaxel to carboplatin/nab paclitaxel.

Tracks 18-19

DR LOVE: Can you comment on your Phase II adjuvant trial evaluating docetaxel/carboplatin?

DR SOCINSKI: We conducted a feasibility study of that combination, and our endpoint was to determine whether we could deliver four cycles of therapy within 12 weeks to more than 80 percent of the patients.

The study included 72 patients and showed that 80 percent of them were able to receive four cycles. We allowed patients to receive growth factor support, and approximately one third of the patients received growth factors at some point during the four cycles.

No treatment-relateOd deaths occurred (Stinchcombe 2007). Our conclusion was that this is a feasible regimen for the patient whom you consider not to be a good candidate for a cisplatin-based approach.

These Phase II safety data suggest that you can use that regimen. The data in our trial were similar to what the CALGB showed with carboplatin and paclitaxel.

Select publications