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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.

Erbitux in Context: BMS 099 and other Trials Before FLEX
Thu, 09/13/2007 - 21:46
Author
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

In my last post, I noted that the FLEX trial of cisplatin/navelbine with or without the EGFR monoclonal antibody erbitux was reported to be positive, demonstrating a significant survival benefit. That's definitely going to have major implications, since our track record for phase III trials of chemo with or without new drug X was very poor for most of the last several years, until the negative streak was broken by the ECOG 4599 trial with Avastin added to carbo/taxol. Here's the older scorecard we had:

Chemo +/- drug X scorecard (Click to enlarge)

Not so good. EGFR inhibitors have been pretty well tested, including both Iressa and Tarceva each in two trials of more than 1000 patients randomized to chemo with or without the EGFR inhibitor, and those trials failed to show a survival benefit overall. But those agents are EGFR tyrosine kinase inhibitors, working on the inside of cancer cells, while erbitux is a monoclonal antibody that works on the outside of the cell against the same target of the EGFR molecule:

EGFR TKI vs MoAb

In one of my earlier posts on erbitux, I described some of the smaller, early trials of chemo combined with erbitux, which were moderately promising but not enough to call a homerun out of the park. There was also the SWOG 0342 trial described in a prior post that tested two schedules of giving carbo/taxol with erbitux that showed a modestly encouraging survival of 11 months overall in both groups, but with a suggestion that the subset of patients who had tumors positive for EGFR by FISH testing fared remarkably better than those who were negative by FISH.

Now we have a glimpse of this positive trial with cisplatin/navelbine. But just last week Dr. Tom Lynch from Massachusetts General Hospital reported on the BMS 099 trial of carbo/taxane (taxol or taxotere at the discretion of the participating oncologist) with or without erbitux (abstract here):

Schema BMS099

The trial was revised a couple of years ago to more than double in size and change from a primary endpoint of response rate to progression-free survival. It completed accrual of 676 previously untreated patients with advanced NSCLC in October of 2006 and did not limit enrollment to patients with EGFR protein expression or overpression by immunohistochemistry or gene amplification by FISH.

Importantly, the differences in side effects were pretty minor between the two arms. Slightly more significant low blood counts and fatigue, but otherwise the main side effects added by the erbitux were an acne-like rash (often on par with or more severe than tarceva), an allergic-type infusion reaction that was severe in about 5% of patients getting erbitux, and significantly low blood magnesium levels (replaceable with oral or IV magnesium), a known side effect of erbitux, in 9%.

We heard the brief summary conclusion of the efficacy results from a press report described in a prior post I wrote in July on this study, that the trial failed to meet it's primary endpoint of improved progression-free survival (PFS) as measured by an independent radiology review committee. We saw the curves for PFS as assessed by both the independent committee and the potentially more biased and non-radiologists investigators themselves, the latter being more favorable for the chemo/erbitux combination:

BMS 099PFS by IRRC BMS 099 PFS by investigators

So both investigators and independent radiologists agreed that the chemo/erbitux patients progressed a little more slowly, but the investigators perceived it as a nearly 25% difference, vs. only about a 10%, non-significant difference in the eyes of the radiology review committee. Not surprisingly, the independent committee also considered the response rate to be a little lower overall than the investigators, and this was the case for both the chemo alone and the chemo/erbitux arms. Both investigators and the radiologist reviewers noted a higher response rate in the erbitux group (5% higher for the investigators, 8.5% higher for the independent committee).

The differences here bring up the issue that progression-free survival and response rate are somewhat soft endpoints, grading systems that can be in the eye of the beholder. Even trial investigators can be subject to a placebo effect and consistently rate their results more favorably than independent reviewers, hence the need for an unbiased committee. But the endpoint of progression-free survival is also limited by the fact you show progression when you do a scan, even though we know people are actually progressing before that. Overall survival is a hard endpoint that isn't subject to debate, and it happens when it happens, not limited by when the study tells you to repeat scans. Because of that, overall survival is the most credible endpoint. But the BMS 099 trial hasn't followed people long enough to report overall survival results yet.

So what can we make of the fact that some of the preceding studies with erbitux, generally combined with carbo and taxol or taxotere, have been only somewhat encouraging on a good day, but the larger, randomized phase III FLEX trial with cisplatin and navelbine in Europe is positive? Well, we could say that the FLEX trial may not show a big difference even if it's statistically positive, but my understanding is that they were looking for at least a 20% improvement in survival, so that would be on par with the benefit with Avastin. If it was that positive, it's likely meaningful. The FLEX trial included only patients with EGFR expression, unlike the SWOG 0342 and BMS 099 trials, that had no restrictions. Because of that, the benefits of erbitux could have been diluted by the unrestricted eligibility. Moreover, we may find from further study of tissue from the BMS 099 and FLEX trials that the EGFR FISH positive patients received a particularly striking benefit from erbitux, but I'm just speculating here. It's also possible that people in the US-based BMS 099 and SWOG trials generally received multiple salvage therapies that diluted any impact from first line erbitux (although you'd still hope to see a robust difference in progression-free survival that isn't clouded by later therapies).

It's hard to speculate on how treatment standards could change in the wake of positive results from the FLEX trial, combined with less impressive results from the carbo/taxane trials with erbitux. Cisplatin/navelbine is very rarely used in the US now, and even in Canada and Europe it has fallen behind other combinations over the last few years. I wouldn't presume that just because erbitux adds a survival benefit to cisplatin/navelbine you should expect a survival benefit with all other platinum-based doublets, since the work with carboplatin and a taxane is decidedly less impressive. Perhaps that's from issues other than the chemo, but we don't know that. Moreover, for the Avastin-eligible patients, I imagine that most of these patients will continue to receive carbo/taxol/avastin. For others, I doubt we'll see a major transition from carbo/taxol to cisplatin/navelbine just to give erbitux with it. But between now and then, we need to see the actual trial results, see what the FDA says, and then see how the dust settles. It's getting increasingly confusing to define the best options for first line advanced NSCLC. But fortunately, that's because after years of the impasse of doublet chemo pretty much producing the same results for everyone, we're now getting new agents that are providing enough benefits that they're pulling us in many different directions. Better to have too many options than too few.

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