Lung Cancer Update, Issue 4

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Alan B Sandler, MD

Tracks 1-12

Track 1	Clinical considerations in the use of first-line chemotherapy/cetuximab in patients with EGFR-overexpressing advanced NSCLC
Track 2	ECOG-E4599: Outcome from first-line carboplatin/paclitaxel with bevacizumab in advanced, nonsquamous cell NSCLC: Analysis of age and gender
Track 3	Predictors of bevacizumab-related hemoptysis in ECOG-E4599
Track 4	AVAiL: A Phase III study of first-line cisplatin/gemcitabine with or without bevacizumab in advanced or recurrent nonsquamous NSCLC
Track 5	Potential for differential efficacy of chemotherapy/bevacizumab combinations
Track 6	Rationale for continuation of bevacizumab upon disease progression

Track 7	Ongoing clinical trials in lung cancer evaluating nab paclitaxel
Track 8	Efficacy of bevacizumab in combination with chemotherapy or erlotinib in patients with previously treated advanced NSCLC
Track 9	Studies of the multikinase inhibitor vandetanib in NSCLC
Track 10	ECOG-E1505: A Phase III study of adjuvant chemotherapy with or without bevacizumab in Stage IBIIIA NSCLC
Track 11	Individualization of adjuvant lung cancer therapy
Track 12	Pemetrexed/carboplatin versus etoposide/carboplatin for extensive-stage small cell lung cancer (SCLC)

Select Excerpts from the Interview

Track 1

DR LOVE: Would you discuss the current treatment options for patients with advanced NSCLC?

DR SANDLER: We have two positive studies evaluating regimens for metastatic NSCLC in somewhat similar groups of patients (Manegold 2008; Sandler 2006), and cisplatin/vinorelbine with cetuximab is now another option (Pirker 2008; [2.1, page 8]). However, three issues need to be addressed with cetuximab. The dermatologic reaction is not a life-threatening toxicity, but it is one that certain patients find difficult to live with. Another issue is the inconvenience of a weekly injection.

Finally, in certain parts of the country, an increased risk of anaphylactic reactions to cetuximab exists, although a recent New England Journal of Medicine article reported on the prospect of identifying patients who may be at risk for anaphylactic reactions (Chung 2008).

Tracks 2-4

DR LOVE: What data sets have been reported in the past year addressing chemotherapy in combination with bevacizumab?

DR SANDLER: A subset analysis of the ECOG-E4599 trial evaluated outcomes for the elderly population because one fourth of the patients on the trial were older than age 70.

A little more toxicity occurred in these older patients, which is not unexpected, but it was manageable. The response rate was better for patients treated with bevacizumab, and progression-free survival trended upward with a p-value close to 0.06 (Ramalingam 2008).

DR LOVE: What do we know about bevacizumab-associated hemoptysis?

DR SANDLER: We learned in the Phase II study (AVF0757g) that patients with squamous cell histology should not receive bevacizumab because of the risk of hemoptysis. We’ve gone back and evaluated data from various studies, including E4599, and only baseline cavitation emerged as a potential risk factor (Sandler 2008).

Interestingly, tumor size and location have not panned out as risk factors. Location may well be part of the squamous cell histology, but it’s difficult to tease the two apart.

DR LOVE: Can you discuss the results of the AVAiL study?

DR SANDLER: The AVAiL study was the European counterpart of ECOG-E4599. It used a three-arm design to evaluate cisplatin/gemcitabine with or without bevacizumab at two different doses, 7.5 mg/kg and 15 mg/kg.

Response rate and progression-free survival endpoints were met in both the bevacizumab arms. Bevacizumab did not add significant benefit to survival, although overall survival was good in all three arms (Manegold 2008; [3.1]).

DR LOVE: If someone were to say to you, “Why not use the lower dose of bevacizumab,” how would you respond?

DR SANDLER: The AVAiL study is compelling. The hazard ratio for progression-free survival was 0.75 with the low dose and about 0.8 with the higher dose, but E4599 is the only study to date that shows a survival advantage, which is with the 15-mg/kg dose (3.1), so I am still administering that dose.

3.1

Track 9

DR LOVE: What do we know about the multikinase inhibitor vandetanib?

DR SANDLER: Vandetanib inhibits both VEGF and EGFR to different degrees. The low dose is more of a VEGF inhibitor, and the higher dose is more of a combination of VEGF and EGFR inhibition.

As a single agent, the higher dose may be better, but in combination with chemotherapy, the lower dose may be preferable because of the potential antagonism between an EGFR agent and chemotherapy. Phase II studies suggest that the addition of vandetanib to either docetaxel or gefitinib may provide benefit (3.2).

3.2

Track 10

DR LOVE: Could you provide an update on the adjuvant ECOG-E1505 trial evaluating chemotherapy with or without bevacizumab (3.3)?

DR SANDLER: This study is evaluating cisplatin-based chemotherapy with or without a year of bevacizumab in patients with tumors of all histologies. The study has a target accrual of 1,500 patients with survival as the endpoint. The study is not accruing nearly as fast as it should, with only about 250 patients enrolled.

3.3

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Neil Love, MD

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David Jablons, MD
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Gregory J Riely, MD, PhD
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Alan B Sandler, MD
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David S Ettinger, MD
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