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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Combinations of Proteasome Inhibitor Velcade with Chemo or Targeted Agents
Sat, 09/01/2007 - 13:25
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

Let's move to combinations of velcade with other anti-cancer agents. My friend, Dr.Angela Davies from the University of California at Davis, led a single-arm phase II trial conducted by the Southwest Oncology Group, SWOG 0339, that evaluated the combination of velcade with gemcitabine and carboplatin (abstract here). A total of 114 patients previously untreated for advanced NSCLC were enrolled. The treatment schedule included the twice weekly schedule for velcade, so patients came in for treatment on four days over the first two weeks, followed by a week to recover blood counts:

Davies SWOG 0339 schedule (Click to enlarge)

Dr. Davies presented the trial at ASCO 2006, where she reported a rather unimpressive response rate of 21%, with stable disease in another 45%, for a total "disease control rate" of 66%. The median response rate was 11 months and one-year survival 47%. While these results were reported to be very encouraging and worthy of a larger phase III trial, the expert who provided commentary at ASCO after that and a couple of other presentations (Dr. Govindan Ramiswamy from Washington University in St. Louis, who is terrific), noted that these results were not an obvious improvement over what we expect to see from doublet chemo alone. Because of selection bias and other factors, it’s very common for phase II trials to demonstrate results that far exceed much bigger phase III benchmarks, only to prove less impressive when tested in a larger setting (this has been a recurring theme in our interpretations of phase II trial results). So a median survival of 11 months in a phase II trial would very likely be expected to produce a median survival of just 8-9 months in a larger phase III trial, exactly what chemo without velcade could do. A larger trial hasn't moved forward at this point, and it's not clear whether one will.

One of the potentially complicating issues with combining chemo and velcade is that there is some work that suggests that chemo and velcade could potentially interfere with each other if given in the wrong sequence. This is a concept we’ve considered already with EGFR tyrosine kinase inhibitors in a prior post. The folks at the University of California at Davis have done a good deal of lab work that suggests that velcade before taxotere may be detrimental, but that taxotere before velcade may lead to a potentiation of anticancer effects.

Velcade Pharmacodynamic Separation

Because these results have only been seen in a lab so far, it’s important to test whether the treatment order really makes any difference in real patients. So this question is actually going to be addressed in a randomized phase II trial being done by the California and Pittsburgh Cancer Consortium. In this trial, all patients with previously treated NSCLC will receive second line taxotere and velcade, at the same doses, and with the only difference being the schedule of treatment. While the concurrent arm will start weekly velcade on the same day as the taxotere (day 1 of a 21 day cycle), the sequential arm will give taxotere on the first day, followed by velcade on day 2 and day 9 of the 21 days schedule:

CPCC velcade trial schema

This trial is actively enrolling at participating institutions (details here).

Of course, chemo isn't the only thing you can combine with velcade. Dr. Tom Lynch, from Massachusetts General Hospital in Boston, reported at ASCO this year on a trial he led that enrolled 50 previously treated patients with advanced NSCLC who were randomized to receive tarceva alone or with weekly velcade(two weeks on, one week off every three weeks). Though not a large trial, the trial was stopped after an early analysis showed that that the combination arm looked no better and actually a little worse, if anything, than the arm that got tarceva alone. Another argument for "don't try this at home" -- more isn't always better. There are no plans to move ahead with a tarceva/velcade combination.

Putting it all together, at this point the jury is still out on whether velcade will emerge from trials as a meaningful contributor for lung cancer, alone or combined with chemo. With a response rate as a single agent comparable to our best agents, and actually with any objective responses of significant tumor shrinkage in previously treated patients, it’s definitely worthy of a good look. But we haven’t seen striking results with combinations thus far. With so many targeted agents being studied in lung cancer and financial and patient resources limited, the results have looked just good enough for the lung cancer community, or Millenium Pharmaceuticals (the company that makes velcade) to consider but not yet commit to large phase III trials that would establish or conclusively end the question of whether velcade is really an effective, helpful drug for lung cancer.

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