You are here: Home: LCU 4 | 2006 : Alan B Sandler, MD

Tracks 1-13

Track 1 Introduction Track 2 Background to ECOG trial E4599: Carboplatin/paclitaxel with or without bevacizumab Track 3 ECOG-E4599: Side effects and toxicity Track 4 Factors associated with pulmonary hemorrhage in patients with lung cancer treated with bevacizumab Track 5 ECOG-E4599 subset analysis of survival by gender Track 6 Prospective correlative assessment of biomarkers in E4599 Track 7 Updated analysis of patient deaths in E4599 Track 8 Clinical implications of E4599 Track 9 NCT00095225: Bevacizumab with chemotherapy (docetaxel or pemetrexed) or erlotinib compared to chemotherapy alone for recurrent or refractory non-small cell lung cancer (NSCLC) Track 10 Potential role for bevacizumab/ erlotinib without chemotherapy Track 11 ECOG-E1505 adjuvant study of chemotherapy with or without bevacizumab Track 12 Development of the EGFR and VEGF tyrosine kinase inhibitor ZD6474 (vandetanib) Track 13 Nanoparticle paclitaxel in the treatment of lung cancer

Select Excerpts from the Interview

Track 8

DR SANDLER: Yes. My specific quote was that this combination in the nonsquamous-cell population included in ECOG-E4599 was the new ECOG reference standard. I certainly would acknowledge that some toxicity associated with the regimen appears greater than with chemotherapy alone, but the benefits that were seen with respect to all the outcomes, including survival, outweigh the risks.

We did not specifically look at quality of life in the study, but it appears that other nonspecific toxicities, such as fatigue, were not increased and that quality of life in fact improved, because in virtually every other study that has shown an improvement in survival, quality of life has been better.

DR LOVE: The trial stipulated that bevacizumab would be continued alone after the chemotherapy until the disease progresses. Do you do that in your practice?

DR SANDLER: Yes, that is exactly what I do. I follow the intent and guidelines of ECOG-E4599. The potential benefit of the maintenance portion of the bevacizumab has been widely recognized. I no longer have any patients actively being treated on ECOG-E4599. I do have one patient who went between a year and a half and a year and three quarters and was on a maintenance dose of bevacizumab, and I have some other patients who had gone not quite that far.

Track 4

DR SANDLER: We submitted a poster that attempted to define prognostic variables for pulmonary hemorrhage (Sandler 2006). It was a case control study in which we combined the data sets from a Phase II study with those from the ECOG-E4599 study and attempted to assess a wide range of prognostic variables to see if one could better define which group of patients was more at risk.

We looked at 22 patients with Grade III or higher pulmonary hemorrhage. Not surprising with the limited number of patients, nothing was statistically significant, but there appeared to be trends for patients with baseline cavitation in their tumors and a history of hemoptysis that predated treatment.

DR LOVE: Hemoptysis wasn’t allowed in the study, correct?

DR SANDLER: Correct. In ECOG-E4599, it was not specifically written into the study at first, but then one or more patients entered the study who had hemoptysis. After the first 60 or so patients, it was put in specifically as an exclusion criterion.

DR LOVE: Oncologists are interested in whether location — peripheral versus proximal — was a factor, and I would also be interested in whether a correlation appeared with tumor bulk.

DR SANDLER: We observed size using three centimeters as a cutoff, and it did not seem to correlate. We noted location, but when radiologists look at what they define as central tumors, it really encompasses a wide range of tumors because I believe their definition is anything that’s more than two centimeters away from the pleural reflection.

In our study, we had an independent radiology group examine all the individual CAT scans — so they were all independently reviewed — and size and location did not seem to matter. We saw a hint that endobronchial disease might be an issue, although that was not statistically significant and it is a very difficult interpretation on a CAT scan, and the results were inconsistent across all the CAT scans and techniques.

Track 9

DR SANDLER: The combination of erlotinib and bevacizumab involves the inhibition of the EGFR pathway along with angiogenesis and was based on a Phase I and II study conducted by Dr Roy Herbst at MD Anderson and my colleagues and me at Vanderbilt, in which we had 40 patients with previously treated nonsquamous-cell, non-small cell lung cancer.

We saw a 20 percent response rate, a roughly seven-month progression-free survival and a 12.5-month median survival (Sandler 2004), but because it was a Phase I/II limited-institution study, a subsequent larger-scale randomized Phase II study was conducted that involved 120 patients and was presented at ASCO (Fehrenbacher 2006).

This study had three arms: Bevacizumab in combination with either chemotherapy (docetaxel or pemetrexed) or erlotinib compared with chemotherapy alone. An improvement in progression-free survival favored the two bevacizumab arms. It was three months on the chemotherapy alone arm and roughly four and a half months on the two bevacizumab arms — 4.4 months with erlotinib and 4.8 months with chemotherapy (1.1).

Track 10

DR SANDLER: That’s an interesting point, and that is my take on this study. It’s another example that the addition of bevacizumab to chemotherapy or, in this case, a biologic, an EGFR tyrosine kinase (TK) inhibitor, such as erlotinib, showed benefit when compared to chemotherapy alone. That’s the first point.

The second point is that it now provides evidence that a non-chemotherapy based approach in the second-line setting consisting of erlotinib and bevacizumab might prove to be equivalent to chemotherapy.

A large Phase III study of more than 600 patients is evaluating erlotinib alone versus erlotinib and bevacizumab in the second-line setting (OSI3364g).

DR LOVE: From the practical or clinical perspective of a physician in practice, what are the implications of these data?

DR SANDLER: That’s another very good question. We do not have official randomized Phase III data for the biologic doublet, but we certainly have enough evidence — more evidence than we have for chemotherapy in the third-, fourth- and fifth-line settings, which we are all guilty of administering.

In clinical practice, this combination would be a bit of a reach at this point. It would be intriguing for those patients who are selected for the use of erlotinib — nonsmokers, Asian patients, patients with EGFR mutations, FISH-positive cases, et cetera.

In our Phase I/II study there was a hint that this combination was working in patients with and without EGFR mutations, smokers and nonsmokers. That has not been broken out yet for the randomized Phase II study, but it’s possible that the combination may allow for the use of the EGFR agent in a broader range of patients.

DR LOVE: What is seen in terms of side effects and toxicity with this biologic doublet, both in terms of data and your own clinical experience?

DR SANDLER: No surprises have occurred in toxicity (1.2). We’re seeing rash, minimal diarrhea associated with the EGFR TK inhibitor, some proteinuria and hypertension related to bevacizumab. Three deaths related to pulmonary hemorrhage occurred on the study — two on the chemotherapy/bevacizumab arm and one on the erlotinib/bevacizumab arm (Fehrenbacher 2006).

Track 12

DR SANDLER: ZD6474 is an oral agent that has both EGFR and VEGF TK inhibition, and it has been involved in two randomized Phase II studies (1.3).

Ron Natale presented a study of ZD6474 compared to gefitinib and demonstrated an improvement in time to progression with ZD6474 (Natale 2006).

John Heymach from MD Anderson presented another study evaluating docetaxel with or without ZD6474, which also showed an improvement in time to progression with the combination, favoring a lower dose in that setting (Heymach 2006).

DR LOVE: Is ZD6474 sort of the oral tyrosine kinase inhibitor version of your doublet of erlotinib and bevacizumab?

DR SANDLER: Correct, that’s the theory.

The interesting aspect is that apparently, depending on the dose, you may see one effect over the other. At 100 mg, the effect appears to be more of an anti-angiogenic one, and that may explain why in combination with chemotherapy the lower dose seems to be better, but the higher dose when used on its own, which has both effects, seems to be better than the lower dose.

DR LOVE: Where do you think we will be heading with this agent? Will we be using it in clinical practice in the near future, and if so, where and how?

DR SANDLER: Randomized Phase III studies are now going forward. If the results are positive, it will become a player in the treatment of metastatic non-small cell lung cancer.

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