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Zactima (Vandetanib) Trial vs. Placebo Negative (for Survival): Details from ASCO
The negative trials don’t get a lot of discussion, but the ZEPHYR trial, a phase III study that directly compared Zactima (vandetanib), an oral inhibitor of EGFR and angiogenesis, vs. placebo, was one that merits some follow-up after my reporting that it failed to show a survival benefit, which was essentially the only thing we learned about the trial prior to ASCO this year. A more complete report of the ZEPHYR trial was presented at ASCO, and though it suffered the indignity of being the rare phase III trial that didn’t get presented during an oral session, I think the results are important enough in trying to assess the real value of Zactima that the results merit being reviewed.
ZEPHYR was the last of four major lung cancer trials with Zactima to be completed and reported. The others are summarized in a prior post, and they showed at best equivocal results. The others are discussed in a point-counterpoint fashion by GRACE member and moderator Neil Berch (arguing that the Zactima glass is half full) and me (taking the less beloved view that the benefits are extremely marginal and probably not enough) — let the record show that, at the present time, his post has been more favored by the people who have added a rating.
SAIL Study Reviews Safety of Avastin in Lung Cancer Among >2000 Patients: Few Surprises (Fortunately)
This morning, Joe provided a link to a story about the Safety of Avastin in Lung cancer (SAiL) study, which is just being published in Lancet Oncology. This is not really a new, original study, but rather a post-approval commitment from Roche to generate a registry of real-life experience using the anti-angiogenic agent Avastin (bevacizumab) in lung cancer patients and document safety: the primary goal is to determine whether new, concerning safety signals occur in a broader clinical practice than the initial, well-controlled studies.
Podcast of Q&A Portion from Molecular Markers Webinar with Dr. Pennell
Here’s the podcast of the Q&A portion of the excellent webinar with Dr. Pennell on Molecular Markers in Management of NSCLC.
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Podcast: Play in new window | Download (37.8MB) | Embed
Thalidomide Fails to Improve Survival in NSCLC
In this week’s Journal of Clinical Oncology the final results of the phase III trial investigating chemotherapy with or without thalidomide in previously untreated NSCLC patients were published. Most people remember thalidomide for the horrifying birth defects (absence of arms and legs, etc) that resulted in the 1960s when pregnant women were given thalidomide for morning sickness. Since this debacle, thalidomide has been a highly controlled substance that has gotten a lot of understandably bad press, and this experience led to a number of necessary changes in the way the government investigates the safety of drugs before releasing them for widespread usage.
More recently thalidomide has become a standard treatment for multiple myeloma, a type of cancer of white blood cells. Much of the efficacy of thalidomide has been attributed to anti-angiogenic effects against vascular endothelial growth factor (VEGF) and fibroblast growth factor, both potentially important targets in lung cancer (we all know the story of Avastin (bevacizumab) in NSCLC, and anti-VEGF antibody). Thalidomide has shown some promise in preclinical models of NSCLC, and has also shown some indications of activity in small cell lung cancer (as Dr. West has covered in the past). It works well in multiple myeloma, but has some potentially worrisome side-effects even if you are not pregnant, principally increased risk of blood clots, constipation, and peripheral neuropathy.
In this most recent study, Dr. Lee and colleagues randomly assigned 722 patients in the United Kingdom with previously untreated NSCLC to either carboplatin and gemcitabine plus placebo or the same chemotherapy plus thalidomide, followed by up to 2 years of maintenance thalidomide (or placebo). The primary endpoint was overall survival. The thalidomide was started at 100mg daily, escalated to 150mg daily in the second month, and the maintenance dose was 200mg daily, a pretty standard dose.
The results were overall disappointing, essentially showing no hint of benefit from the addition of thalidomide in the overall group. The response rates were the same in the two groups (40% and 42% for thalidomide and control). The median overall survival of the thalidomide and control groups was 8.5 and 8.9 months.
PFS and Overall Survival Curves
In addition, the group decided to do a post-hoc (after the fact) subgroup analysis by tumor histology. We know that certain drugs, like pemetrexed, seem to have different effects on different types of NSCLC, so why not thalidomide? In fact, there did appear to be worse outcomes in the non-squamous patients treated with thalidomide, with only 8% of patients on thalidomide surviving at 2 years compared to 18% on placebo. In the squamous cell patients, however, it was just the opposite, with 20% of patients on thalidomide surviving 2 years compared to only 12% on placebo. It is hard to know how much weight to give this small but statistically significant difference. Continue reading
Why Avastin is a No-No for Patients with Squamous NSCLC: A Brief History
At the time that OncTalk (the predecessor to GRACE) was just getting off the ground in the fall of 2006 (wow, three years have gone quickly!), Avastin (bevacizumab) was just getting FDA approval in the first line treatment of advanced NSCLC. The main focus was on the randomized trial that showed a survival benefit and led to its approval, and in the rush to generate summaries of the treatment highlights for various treatment settings in lung cancer, the story of Avastin skipped over its development in lung cancer. Many people may know that Avastin is given only in patients with non-squamous cancers, but it’s worth backtracking to understand why.
The first significant trial of Avastin in NSCLC was a randomized phase II trial done at Vanderbilt University and that enrolled about 100 patients with advanced NSCLC who received either chemotherapy with carbo/taxol (paclitaxel) alone every three weeks., or the same chemo with Avastin at either 7.5 or 15 mg/kg IV every three weeks. This trial was open to patients with any NSCLC histology. Importantly, patients who were enrolled on the chemo only arm as first line therapy were allowed to cross over to the Avastin alone (at the higher dose) after progression on carbo/taxol.
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The Shifting Ground in Advanced NSCLC: A Quick Survey of the Experts
Although there has always been lattitude for individualizing treatment, I think developments in the last few years have added so many options that pretty much any standards we had from a few years ago have eroded. Particularly in a world in which the eligibility for avastin (bevacizumab) has is debatable (with growing experience of little risk when treating patients with brain mets, on coumadin, etc.), some less impressive results on the AVAiL trial with cis/gem +/- avastin, marginally positive results with erbitux (cetuximab), and a complete free-for-all in the transition from first line to second line (timing? maintenance?).
I thought it would be interesting to take the pulse on where the experts were, since my sense is that there’s a lot of variability in how people are interpreting the data now. I sent an e-mail to about 30 expert colleagues from around the country and different institutions, with a simple thumbnail sketch of a fairly typical patient and asked specific questions of what treatment they would recommend as first line therapy, when they would stop it, and whether they would continue a maintenance therapy or switch to a new treatment, and if a new treatment, when. I also asked whether they would send any molecular markers. Here’s the thumbnail sketch of the patient:
A never-smoking Caucasian 62 year-old woman has a cough, sees her MD, found after full workup to have a lung adenocarcinoma metastatic to lungs, liver, adrenals on PET/CT. Brain MRI shows multiple sub-centimeter asymptomatic brain mets without edema. She is referred to you for systemic therapy after seeing a rad onc, getting whole brain irradiation. Her PS remains good, kidney function fine, insurance would cover anything (this is something that can limit our treatment decisions). Summary: A healthy, motivated Caucasian woman with advanced adenocarcinoma of the lung, recently treated asymptomatic brain mets. And though I asked whether people would want to send for molecular markers, I limited responses to clinical variables, for the sake of argument I asked them to presume that there adequate tissue for this, and/or the patient refused another biopsy.
ATLAS: Another Trial Shows Benefit for “Maintenance”/Early Second Line Therapy
A press release today informs us that the ATLAS trial of maintenance avastin (bevacizumab) combined with tarceva (erlotinib) vs. avastin with placebo was positive for a significant improvement in progression-free survival (PFS). We had already learned that the very similar SATURN, of maintenance tarceva vs. placebo in patients who weren’t on avastin was also positive for an improvement in PFS (see prior post), though we don’t have details yet. Here’s the design of these two trials:
(click to enlarge)
What we’ve learned so far about the ATLAS trial is that an interim planned analysis of safety and efficacy showed that there was a significant improvement in progression-free survival that led to the stopping of the trial and disclosure of these early results of more favorable PFS in the recipients of tarceva combined with avastin. It had already enrolled 1157 patients, which was its goal, and these patients received avastin with any of several different platinum-based chemotherapy doublets (carboplatin/gemcitabine, carboplatin/paclitaxel, carboplatin/docetaxel, cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine). If patients hadn’t progressed after four cycles of this combination, they would be randomized to avastin maintenance with either tarceva or a placebo pill. The results apparently showed no evidence of any unexpected safety problems, which is important both for broadening our experience of different chemo agents with avastin and because patients with therapeutic doses of blood thinners were able to be enrolled, as were patients with more peripheral squamous cancers that were far from the center of the chest (a minority of squamous cancers).
Angiogenesis in First Line Advanced NSCLC: Focus on Avastin (Bevacizumab)
Video presentation describing the concept behind angiogenesis and the evidence on the anti-angiogenic agent avastin (bevacizumab) in NSCLC.
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Or access via web link here.
Slide/figure images from the video presentation are available as a pdf here: Angiogenesis FL Adv NSCLC Vodcast images
Transcript is here: Angiogenesis FL Adv NSCLC Vodcast Transcript
Podcast: Play in new window | Download (33.0MB) | Embed
Incorporating Tumor Cavitation into Response Assessment
As I described in a post last year, one of the common features of angiogensis inhibitors is that lesion often cavitate, shrinking not only from the outside in, but hollowing out and dying from the inside out. One of the concerns has been that cavitating lesions may be at higher risk for bleeding, but the work I described in the prior post suggested no clearly increased risk of severe bleeding complications among patients who develop tumor cavitation on anti-angiogenic agents. But another issue is that tumor cavitation may be a relevant measure of response that is being missed by out current systems of measuring response by only assessing the outer dimensions of a tumor.
Investigators in Ontario, Canada looked at this issue by assessing the frequency of this cavitary response in a couple of recent trials they ran through the National Cancer Institute of Canada (abstract here). This report looked retrospectively at 33 patients who received doublet chemo with an antiangiogenic agent (in this case, the oral VEGF inhibitor cedirinib, also known as AZD-2171) and found that 8 (24%) experienced tumor cavitation during treatment. This wasn’t seen in any of the 18 patients treated with chemo alone on another trial of chemo alone that ran over a similar time line in Canada (and it’s rarely seen with chemo alone in general).
A typical situation is shown in the figure below, in which a mass doesn’t change outer dimensions, but it hollows out early in treatment, then progresses by the filling in of the center of the tumor.
It’s probably very relevant that the overall volume of viable cancer has decreased substantially early in treatment, but that response isn’t captured by our current system. Nor is the clear increase in tumor bulk as the cancer grows internally, since outer dimensions again don’t change.
The investigators tested how many patients would have experienced a change in their official response if an alternative definition of response was used in which tumor measurements included not just outer dimensions but subtracted the hollowed out portion of any cavitating lesion. And progression would be defined not only by outer dimensions but by the filling in of cavitation:
When they did tumor measurements by both the current standard (outer dimensions only) and the new alternative that incorporates measurement of the tumor cavity, a few of the patients had differences in their response assessments, going from stable disease to a partial response, or from stable disease to progression. They started with small numbers of patients and just assessed these issues retrospectively, so you really couldn’t say anything definitive. But it was interesting to see that the current system probably misses some meaningful anti-angiogenesis-induced responses and can keep people on an ineffective therapy for too long while they progress within the stable shell of a tumor.
The invstigators suggested that this new technique needs to be tested in trials moving forward, and I agree. But even this early work could be useful
Tales from the Clinic: Mucinous BAC
In my last post I outlined the typical clinical scenario for pneumonic bronchioloalveolar carcinoma (BAC), which is typically the mucinous subtype of this unusual disease. In fact, we are still actively learning a great deal about BAC, enough for the lung cancer experts to begin to develop a more sophisticated view that the mucinous and non-mucinous subtypes have different behaviors and respond differently to treatments. Here is a case that illustrates a situation that I would consider to be typical for the mucinous, pneumonic form of BAC.
Ella A. was 74 year-old woman with a very long smoking history of about 50 years, who quit last month in the face of worsening pulmonary and other symptoms. Specifically, she experienced an initial dry cough that became productive of sputum over a six-month period, during which time she also developed increasing shortness of breath and a 20-pound weight loss for a woman who was pretty slender beforehand. This led her to her primary care physician, which showed extensive “consolidation”, shadows in both lungs and particularly extensive on the left. These findings were confirmed on a CT.
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As you might suspect, this led to a referral to a pulmonologist for a brochoscopic biopsy. The pulmonolgist needed to start her on oxygen before he could do a thorough bronchoscopy. The biopsy revealed well differentiated BAC, but the pathologist (an expert in lung pathology) didn’t have enough material to specify whether it was mucinous or non-mucinous.
Frankly, at the time when I first met her, in December of 2006, there were only the early inklings that this could be relevant. We don’t have much more information since then, except for the anecdotal experiences of myself and a few others who treatment many patients with BAC, which have corroborated the early impression that the well described effectiveness of oral EGFR inhibitors like iressa (gefitinib) and tarceva (erlotinib) in BAC appeared to be limited to the non-mucinous subtype.
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