Doubts Raised About Avastin’s Benefit in Older Patients with

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Doubts Raised About Avastin’s Benefit in Older Patients with Advanced NSCLC

April 27th, 2012 - by Dr. Jack West

http://blog.lungevity.org/2012/04/27/do ... ced-nsclc/

In a very recent publication in the Journal of the American Medical Association (JAMA), a group from Dana Farber Cancer Institute in Boston reported that the targeted anti-angiogenic agent Avastin (bevacizumab) may provide no meaningful benefit when added to chemotherapy in older patients with advanced non-small cell lung cancer. To provide some review on this controversial topic, Avastin was studied in a randomized phase III study called the ECOG 4599 trial and found to lead to a survival benefit when it was added to carbo/Taxol in Avastin-eligible patients. This group of “Avastin-eligible” was a limited subset generally defined by a good performance status (active, generally healthy), no brain metastases (an initial requirement that has been relaxed with more experience showing no markedly increased risk of bleeding in the brain in patients with treated, asymptomatic brain metastases), no significant hemoptysis (coughing up blood), and non-squamous NSCLC histology — the latter two being exceluded because of an identified high risk of life threatening or fatal hemoptysis in patients with squamous NSCLC or a history of coughing up more than a very scant amount of blood.

The positive trial led to the approval of Avastin by the US FDA in late 2006 for addition to carbo/Taxol in advanced NSCLC for the eligible subset of patients, but there have always been nagging questions as to how much benefit it really offers, particularly in older patients. A post-hoc subset analysis of the ECOG 4599 trial indicated that patients 70 and older who received Avastin derived no survival benefi, likely because they experienced disproportionately greater side effects than younger patients from the addition of Avastin. Meanwhile, another randomized phase III trial done in Europe with a different chemotherapy backbone, called AVAiL (AVAstin in Lung cancer), demonstrated a relatively unimpressive though statistically significant improvement in response rate and progression-free survival when Avastin was added to cisplatin and gemcitabine, but AVAiL showed no benefit in overall survival.

Following its FDA approval, Avastin has been recognized in the oncology community as a standard of care, but not unquestionably the standard of care; in fact, only about 20-25% of patients in real world cancer care in the US actually get it. The reason it is incorporated for only a minority of patients remains debatable and is likely due to several factors. I think that when there are many well-established exclusion factors, and then you need to factor in several “relative contraindications” — for example, cancer growing near blood vessels that could pose a higher bleeding risk, or a poorly differentiated cancer that is suspected may be of squamous histology — the actual proportion of patients who remain good candidates for Avastin could well be less than 40%. Beyond the question of eligibility, there is also the issue of whether the positive results of the ECOG trial definitely outweigh the absence of survival the AVAiL trial and the absence of a survival benefit in older patients on the ECOG trial. It’s also important to remember that the median age of newly diagnosed lung cancer in the US is ~71, meaning that more than half of patients with advanced NSCLC are in an age range where the value of Avastin is particularly questionable.

It is in this context that the JAMA publication emerges and further challenges the possible role for Avastin in older patients with advanced NSCLC. In contrast to a carefully regulated clinical trial, this work analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database, a large collection of data from a wide range of patients from 17 cancer registries in multiple states. This is a reflection of cancer care as it is truly prcticed, and this is something that is less controlled — potentially both a strength and a weakness. Though there are many uncontrolled variables in this analysis, this kind of database offers a broad view of a large population of real world patients, To me, therefore, it qualifies as another valuable tool that can complement carefully controlled clinical trials with highly selected patients, albeit with plenty of shortcomings.

This particular analysis reviewed retrospective data from Medicare claims in the SEER database from patients 65 or older with non-squamous NSCLC histology and a few other specific eligibility issues, who were diagnosed 2002-2007. This study then compared results for patients before the availability of Avastin to the results for patients who received treatment after the availability of Avastin in late 2006; it also looked at results of patients in the latter time frame, depending on whether those patients received Avastin or not. In terms of actual numbers, from the latter time period (2006-2007), they had results from 318 patients treated with carbo/Taxol/Avastin to compare with those from 1184 patients who received carbo/Taxol without Avastin , and they also had a group of 2666 patients who had received carbo/Taxol from 2002-2006.

The investigators reported that patients who received chemo/Avastin with were more likely to have fewer other medical problems and more likely to have well or moderately differentiated cancers than the patients in the same time range who received chemotherapy alone. Despite these generally more favorable features, they did not demonstrate a superior overall survival (OS).

(Click on link above to view image)

Specifically, the median survivals for the three main groups were 9.7 months in the chemo/Avastin patients (one year OS 39.6%), 8.9 months in the chemo alone patients in 2006-2007 (one year OS 40.1%), and 8.0 months for patients receiving chemo alone starting in 2002-2005 (with a one year OS 35.6%). In the end, they performed multiple different analyses of the numbers, but they all demonstrated no clinically significant differences favoring addition of Avastin to standard chemotherapy in this population of patients over 65 with advanced non-squamous NSCLC.

One of the potential challenges to interpretation of a retrospective review of clinician-assigned treatments is that there are presumably unmeasured variables that are distributed differently between those patients who were prescribed Avastin and those who were not. For instance, performance status and perceived risk for bleeding are rather subjective judgments by a clinician, and patients who were more proactive in seeking more aggressive vs. less aggressive care were probably more likely to be given Avastin with chemo. However, if anything, patients who are perceived as better candidates for Avastin are, if anything, a particularly more favorable group, so any differences of unmeasured variable would favor a better survival in these patients, I strongly suspect

This leads us to a question of what to do with this information.. There has been some speculation that payers may not cover Avastin in older patients, but it is too early to see what happens. These data certainly corroborate the pre-existing data questioning a benefit from Avastin in patients over 70, so we may see less and less enthusiasm for it being used in this age group. At the same time, if payers develop a policy of not covering it in older patients, this will have a profound impact, and it will be hard to appeal such a decision based on evidence. For patients in the 65-70, we still have data from the ECOG trial that showed a demonstrable benefit in patients younger than 70, and I think it’s appropriate to consider the group of 65-70 separately from those who are older. Importantly, the data from the JAMA paper included only 318 patients in the Avastin group, so with the limitations of this work, I personally consider those results to be of lower quality than the results from the ECOG 4599 trial. My inclination for now is to continue to recommend Avastin for patients under 70 who are otherwise eligible, but it will be important to see whether there is increasing resistance to covering it based on these results.