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Fotolyn (Pralatrexate) Chemotherapy Beats Tarceva on Survival as Second Line Therapy in Smokers
It’s been two and a half years since I described a phase IIB trial of Fotolyn (pralatrexate), a relatively new chemotherapy agent, being compared to Tarceva (erlotinib) in current or ex-smokers with previously treated advanced NSCLC. The new drug, Fotolyn, is described in a prior post, and it has since been approved by the FDA as a treatment for peripheral T-cell lymphomas, so it’s commercially available in the US. Today, Allos Therapeutics, the company that makes Fotolyn, sent out a press release that the clinical trial is positive for a modest survival advantage vs. Tarceva in this trial of current and former smokers.
A total of 201 patients were enrolled, with a 13% improvement in OS in the overall population (166 included for analysis). In addition, there were some predefined patient groups for subset analysis, which demonstrated that light smokers (I don’t have the precise definitions for light vs. heavy smoking history) did particularly better with Fotolyn (HR 0.63, corresponding to a 37% improvement), as did patients with non-squamous cancers (HR 0.65, corresponding to a 35% improvement). They saw trends in favor of Fotolyn for overall survival in all groups except those with squamous NSCLC and those who received prior Alimta (pemetrexed).
Post-ASCO Discussion of the BR.19 Trial
Here’s the first of a series of posts on key presentations on lung cancer from ASCO 2010, as reviewed by myself and Dr. Nate Pennell of our faculty here several weeks ago.
The first topic we covered was the very interesting if troubling Canadian BR.19 trial of post-operative Iressa (gefitinib) vs. placebo, as summarized by Dr. Pennell.
Dr. Pennell: So this is certainly one of the most important presentations at ASCO this year, I think, if nothing else to show us that we aren’t nearly as smart as we think we are. Gefitinib, as I’m sure most of our GRACE community knows, is an EGFR tyrosine kinase inhibitor very similar to Tarceva, which is the approved drug here in the United States. And back in the early 2000s there was a lot of enthusiasm for exploring the potential for gefitinib in the adjuvant setting for patients with early stage disease to see if it improved cure rates essentially.
And so the BR.19 trial was launched in the first half of that decade in resected patients with stage I-B through IIIA non-small cell. These patients could receive adjuvant chemotherapy as appropriate, I think, once the adjuvant chemotherapy trials in 2003 and 2004 came out and then were randomized in one-to-one fashion to either two years of daily gefitinib or to placebo.
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Physician Researcher Discredited, Potential Implications for Lung Cancer Research
Lest we think that media-driven self-immolation is reserved only for people Like Mel Gibson and Lindsey Lohan, this week we saw a little more drama than we prefer to see in the world of medical research, touching quite close to home. Following a rather stunning article in the low budget but tenacious Cancer Letter (primarily read by cancer and pharma/biotechl industry insiders), the New York Times ran a more widely publicized story about a highly regarded young researcher from Duke, Dr. Anil Potti, who allegedly lied about his being awarded a Rhodes Scholarship, and whose research on genetic signatures of lung cancer has recently been questioned after being published in the New England Journal of Medicine and several other very high-tier journals.
I know Anil, and he seems to be a good guy, but if the allegations are true, and it appears from the evidence, even if it’s not the type of evidence we usually discuss here, then he went too far in the more common practice of “resume padding” that so many people do by exaggerating their experience a bit or calling their student role a “pre-doctoral fellowship”. Not surprisingly, saying you won something as prestigious and verifiable as a Rhodes catches up with you, and his applications stopped mentioning this a few years ago, but it was too late. His reputation and the work he’s done at Duke have all been discredited, his research suspended, and a payments from a large grant of $729,000 from the American Cancer Society have been suspended.
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.
The Work We Still Need to Do
I just gave a continuing medical education talk to a group of general physicians at an out of town community hospital, and in that process I stepped out of my bubble. Spending most of my life working with cancer patients, oncologists, and other physicians at my own tertiary hospital, I primarily encounter people who share a commitment to dedicating resources and a great deal of research effort to cancer patients in general, including lung cancer. While we know that there is a terrible lack of awareness that lung cancer is the leading cause of cancer death in the US (about 28% for both men and women) and that it’s woefully underfunded, we’re all preaching to the choir here. In my talk today, though, to physicians who don’t have a particular focus on or interest in cancer, I was saddened and disappointed that I was interrupted so that someone could ask why we’re even treating people who continue to smoke and whether our treatments are beneficial enough to treat people with metastatic lung cancer at all.
To some, having the limitation of not offering curative therapy, especially if we’re considering expensive treatment, makes it tempting to be derisive that treatment is of value. We see far more patients with improvements in survival measured in years, but even if it’s months, the vast majority of my patients consider a survival benefit of “good time” with minimal side effects to be exceptionally valuable. The irony is that its often physicians who will be tenacious about pursuing every treatment that is remotely useful, and then many others beyond that, without a remote concern about the costs for the health care system, if it’s their family member affected. But in the abstract, people who I expect would be more sensitive and insightful can be painfully nihilistic.
There have been a few recent trials that have demonstrated that a surprisingly high proportion of people diagnosed with lung cancer are never referred to another physician for treatment. As oncologists, it’s hard for us to imagine why we wouldn’t be offered the opportunity to at least discuss the potential value of treatment. But today I saw a glimpse of the mindset of “why bother?”.
Case-Based Webinar Discussion on Molecular Marker Studies, Sequence of Treatments in Advanced NSCLC
Our practice in managing advanced NSCLC has been evolving rapidly as new studies emerge highlighting the importance of molecular markers in guiding treatment decisions and leave open questions about how to optimize the sequence of treatments from first line to second line, who to observe and who to recommend for maintenance therapy. And if maintenance therapy, what treatment to recommend?
If the ongoing debate have been leaving you without clear answers, join me with two other national experts to discuss how each of us approaches real life clinical situations in terms of what molecular markers we would obtain in different situations, what first line therapy we’d recommend, and how we would transition from first line to later treatments. On Wednesday, July 28th, 8 PM EDT/5 PM PST, I’ll be joined by Dr. Tom Hensing from Northshore Health Systems in Evanston and affiliated with the University of Chicago, as well as Dr. David Jackman from Dana Farber Cancer Institute in Boston as we hash out ideas together.
We may not arrive at a complete consensus, but we’ll cover the range of approaches and the current state of what is known and what remains to be decided. The event is free but limited, and you need to register in advance. We’ll plan to edit the program into a series of podcasts afterward.
Basics of Bronchioloalveolar Carcinoma (BAC)
Bronchioloalveolar carcinoma, or BAC, is a unique subtype of non-small cell lung cancer (NSCLC) that has unique features in terms of the demographics of who gets it, how it appears on scans, how it often behaves, and potentially in how it responds to treatment. It is a subset of lung cancer for which most of what we know emerged in the last 10 years, with our understanding of this entity, and even the definition of BAC, still evolving.
What is BAC?
BAC was first identified and defined as a separate subtype of lung cancer by Dr. Averill Liebow in 1960. At that time, he highlighted it as a form of well differentiated adenocarcinoma of the lung that appeared to not be able to invade the surrounding lung scaffolding and spread within the lung(s), presumably aerogenously and/or through lymphatic channels.
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NATCH: Good Question, Bad Trial
As I mentioned in my last post on the recent results on pre-operative (neoadjuvant) chemotherapy, the results of this work failed to achieve statistical significance but did appear to be associated with a degree of benefit comparable to the magnitude of benefit seen with post-operative (adjuvant) chemotherapy, but the neoadjuvant trials were smaller and therefore underpowered. At the same time, there are differences in the patients who receive neoadjuvant vs. adjuvant chemotherapy. Specifically, the patient population getting pre-operative treatment are a broader population that hasn’t had the patients with the most aggressive disease or marginal performance status drop out before getting to the post-operative therapy part. The patients enrolling on adjuvant therapy trials had to have gone through surgery, tolerated it OK, been found to not have more advanced disease, and still feel up to pursuing more treatment: they’ve already cleared several hurdles.
The best way to directly compare a pre-operative to a post-operative chemotherapy strategy is to directly compare the same patients randomized in the same trial. This was the premise of the Neoadjuvant vs. Adjuvant Taxol/Carbo Hope (NATCH) trial, which randomized 624 patients to either surgery alone, carbo/taxol for three cycles pre-operatively, or the same chemo post-operatively. Enrolled patients could have anywhere from stage IA (with at least a 2 cm tumor) to stage IIIA N2 NSCLC.
ASCO Update on Pre-Operative Chemotherapy
Post-operative, also known as adjuvant chemotherapy, is the established method for delivering systemic therapy to improve long-term outcomes beyond what surgery alone can deliver. An alternative approach, though, is to give treatment prior to surgery. This gives the potential advantage of treating potential micrometastatic disease at the earliest opportunity, identifying the response to treatment given rather than treating “blind” with no disease to follow, and potentially delivering treatment more reliably because more patients will receive treatment as planned than in the post-operative setting, where many patients may drop out of consideration for chemo as they contend with recovering from surgery and potentially having complications.
Still, the higher profile pre-operative chemotherapy studies haven’t been positive, or at least not positive enough. But it’s worth reviewing what’s being considered a negative study.
First, there was the SWOG 9900 trial, designed with a plan to enroll 600 patients to detect the differences they hoped to, but closing after only 354 were enrolled, in the face of a series of positive post-operative trials making it very difficult to continue to enroll patients on a trial of pre-op chemo vs. up front surgery, with no plan for adjuvant chemotherapy. This trial, for patients with stage IB – IIIA NSCLC (without N2 nodal disease, a higher risk group), gave 3 cycles of pre-operative carboplatin/Taxol (paclitaxel) and was reported as showing a non-significant trend toward more favorable survival in the chemotherapy recipients. Results are illustrated on the curves for progression-free and overall survival shown below:
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Though these differences were not quite statistically significant, they both reflected an approximately 20% improvement with chemotherapy compared with surgery alone. Though some have speculated that these results may have been more favorable if a cisplatin-based regimen were used, the magnitude of relative improvement here with carbo/taxol seems very comparable to the results we’ve seen in positive adjuvant trials with cisplatin-based regimens, but the trial was definitely underpowered, closing with just under 60% of their intended patient enrollment completed.
Case Discussion with Dr. Nasser Hanna: Managing Extensive Stage Small Cell Lung Cancer
Here is the last case I discussed several months ago with Dr. Nasser Hanna, lung cancer expert at Indiana University. After two cases that included never or light former smokers, which he joked that I saw far more of than he did, we changed direction to cover current issues in managing extensive stage small cell lung cancer, a field in which he’s been a leader.
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Dr. West: Let’s turn to a final case: a 57-year-old currently smoking woman, with a 50 pack year smoking history, who first developed malaise and a cough about 6 months prior to her presentation. She felt her symptoms may have spontaneously improved transiently, but 6 weeks prior to her presentation, she developed non-exertional left chest pain and slight hemoptysis. She was not short of breath, had no weight loss, and she presented to her primary care physician and was found to have an abnormal chest x-ray followed by a CT.
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