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Vascular Disrupting Agent ASA404 Fails in First Line Phase III Trial for Advanced NSCLC
Unfortunately, yesterday brought bad news in the form of another negative phase III trial for advanced NSCLC, this one the ATTRACT-1 trial of carboplatin/taxol (paclitaxel) with or without ASA404, which is in a class of drugs called “vascular disrupting agents” that I described in a post back in 2007. There had been a phase II trial of this combination with ASA404 that looked very promising, with a median overall survival of 14 months for the combination arm, vs. only 9 months for the arm getting chemo alone. This led to a couple of larger, more definitive studies that have been ongoing. The first, ATTRACT-1, was in the first line setting, and as noted above gave ASA404 on a backbone of carbo/taxol, and has completed enrollment. The second, ATTRACT-2, is still accruing patients and is giving taxotere (docetaxel) with or without ASA404 in the second line setting.
The news yesterday was that the ATTRACT-1 trial is being halted (no more treatment with the study drug, and people are no longer required to adhere to treatment according to the protocol-based plan), because an interim analysis of the trial results showed that the investigational arm wasn’t doing any better than the standard chemo arm, and it appeared that there was no way for this to improve to the point at which ASA404 would confer a survival benefit. We don’t have more details available than that, though this was enough information to lead shares of the UK-based company Antisoma, who make ASA-404, to lose 2/3 of its value over the day. Novartis had been co-developing the drug with Antisoma.
Q&A Session with Dr. Ramalingam on Personalizing Treatment Recommendations for Advanced NSCLC
The second podcast from Dr. Ramalingam’s excellent webinar on Personalizing Treatment for First Line NSCLC is the question and answer session that followed it, which includes many questions about EGFR-based therapy, antiangiogenic agents, and other relevant issues for individualized treatments for patients.
Here is the audio and video versions of the podcast, along with the figures and transcript for it.
ramalingam-personalizing-first-line-nsclc-therapy-qa-transcript
ramalingam-personalizing-first-line-nsclc-therapy-qa-transcript
ramalingam-personalizing-first-line-nsclc-therapy-qa-figures
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Dr. Suresh Ramalingam on Personalizing First Line Therapy for Advanced NSCLC: Podcast Available
I’m very pleased to offer the excellent podcast produced from the recent webinar by Dr. Suresh Ramalingam, a leader in the lung cancer field who heads the Thoracic Oncology Program at Emory University in Atlanta. He’s also a good friend I’ve known since our fellowship training days, and he was kind and generous enough to refuse the honorarium we offered for his participation, instead requesting that it be donated back and used for other GRACE programs. Instead, he was happy to do this entirely out of a commitment to the lung cancer community. This is part of a small series of programs supported by an educational grant from Eli Lilly, so we are now enabled to do an additional program because of his generosity.
His webinar provides a very brief historical overview of NSCLC in general and then advanced NSCLC in particular, including a historical perspective of the evolving standards of care first with chemotherapy alone, and then with the integration of targeted therapies. He describes how our approach now individualizes our treatment recommendations based on such issues as particular NSCLC histology, molecular factors, performance status, and sometimes age to offer what we hope will deliver the best combination of efficacy and safety for a patient.
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Abraxane Bests Taxol in Response Rate for NSCLC: What Might this Mean?
In addition to developing new agents or refining which patients should or shouldn’t be given to particular patients, another way to potentially gain ground in fighting cancer is to improve the tolerability of a standard treatment in a way that either makes it more effective or reduces side effects, thereby making it possible to give higher doses. The drug Abraxane (nanoparticle albumin bound paclitaxel) uses the approach of coating taxol with albumin to reduce the side effects associated with standard taxol (paclitaxel), making it possible to give it without steroids (which can be a rather bothersome issue for many patients, causing problems from severe insomnia to very high blood sugars and more) and also reduce some other taxol-associated side effects like joint and muscle aches (see prior post on Abraxane for more background information). It’s also possible to give doses that may be high enough to work better than standard taxol. Abraxane has been approved in breast cancer since 2005, and it’s used here and there in lung cancer, but there is relatively little data about it in lung cancer. However, earlier this week, it was reported that a large trial of carboplatin/Abraxane vs. carboplatin/taxol for initial treatment of advanced NSCLC was “positive”, at least in terms of showing a significant improvement in response rate. But what does this mean for the field of lung cancer?
The short answer is that we don’t know because we need much more information, to be presented at the large ASCO meeting in early June, to really be able to assess the impact that this trial should have. For starters, response rate isn’t the most important endpoint in lung cancer, and I would consider it to be of relatively little importance compared with overall survival, tolerability/quality of life, and progression-free survival. Response rates represent the proportion of patients with tumor shrinkage beyond a strict set of criteria, but there are many reasons that the impact of a treatment may be dissociated from response rate. You’d definitely prefer to see major tumor shrinkage in more patients rather than fewer, but some treatments like the EGFR inhibitor Tarceva (erlotinib) or the investigational ALK inhibitor crizotinib (PF-02341066) may have a relatively or extremely low response rate in a broad population but be hugely effective in that group in which the cancer shrinks.
Recent Webinar with Dr. Weiss on Potential Use of Post-Operative Tarceva Available
Here’s a podcast from the webinar presentation earlier this month by our beloved Dr. Weiss, covering the open question of whether we should consider giving an EGFR inhibitor like Tarceva (erlotinib) as an adjuvant (post-operative) therapy following potentially curative surgery for early stage NSCLC. It’s a setting in which there is a good rationale if we extrapolate from the setting of metastatic NSCLC, at least for patients with an EGFR mutation, but we’ve made incorrect presumptions before when we extrapolate.
Dr. Weiss reviews the pros and cons and the scant relevant data in his podcast. Below you’ll find the audio and video versions of his presentation with Q&A that followed, as well as the figures and transcripts that go with this.
weiss-adjuvant-egfr-tki-webinar-audio-podcast
weiss-adjuvant-egfr-tki-webinar-figures
weiss-adjuvant-egfr-tki-webinar-transcript
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Expert Case Discussion: Treating the Patient with a “Precocious Metastasis” with Curative Intent
Here is the last of three interesting cases I discussed with Drs. Alex Farivar, thoracic surgeon at Swedish Cancer Institute here in Seattle, and Anne Tsao, medical oncologist at MD Anderson Cancer Center in Houston. This particular case is a man I saw a few years ago, with a solitary brain lesion and what otherwise appeared to be a very isolated lung cancer in the right upper lobe. His case brings up issues of the feasibility of treating someone with a solitary lesion with curative intent.
Here is the audio and video versions of the discussion, along with the transcript and figures.
rt-farivar-tsao-case-3-precocious-met-audio-podcast
rt-farivar-tsao-case-3-precocious-met-transcript
rt-farivar-tsao-case-3-precocious-met-figures
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The Predicament of Poorly Differentiated NSCLC/NSCLC NOS
A topic that came up in a recent expert round table case discussion was the issue of how to manage a patient with a lung cancer for which the pathology report says “NSCLC not otherwise specified (NOS)”, or “poorly differentiated NSCLC, NOS”. What does this actually mean, and what does it mean in terms of treatment options?
Tumors of pretty much all types are categorized by their tumor grade, how “differentiated” they are, which basically means, “how much do the cancer cells look like the cells they started out as?”. Different cells of the body start out as stem cells, which means that they’re not specialized to be any special kind of cell, like one that detects light in the back of the retina, lines the esophagus, or is optimized for lung function. Most cells of the body are differentiated, so that the appearance under a microscope shows that it’s a liver cell, part of the kidney filtering mechanism, heart muscle, etc.
Cancer cells, however, have mutations in them that make them grow and divide faster than other cells (that’s why they make a tumor that pushes other tissues aside), and they usually have several. As they grow and divide, they often make sloppy copies of their DNA that leads to more mutations. Cancers therefore are made of cells that may look a lot like the normal cells they originated from (well-differentiated), or they have lots of mutations that make the cells look so chaotic that they don’t look at all like the cells they started out as (poorly differentiated).
Today, oncologists want to know whether a non-small cell lung cancer (NSCLC) is an adenocarcinoma, squamous cell carcinoma, large cell neuroendocrine carcinoma, etc. But about 20% of the time on various studies, we get an answer back of “NSCLC not otherwise specified”. As explained by Dr. Matt Horton, expert lung cancer pathologist, a lung tumor may be classified as NSCLC NOS because of either of two reasons:
1) there isn’t enough tissue, because the biopsy material was very scant, or
2) the tumor is so poorly differentiated that even with all of the material in the world, a good pathologist couldn’t identify the underlying NSCLC histology
Case Discussion with Experts, Drs. Julie Brahmer & Greg Riely, Part 1
Here’s a webinar case discussion I did with Drs. Julie Brahmer from Johns Hopkins in Baltimore, and Greg Riely from Memorial Sloan Kettering Cancer Center in New York. They’re great thoracic oncologists as wellas friends, and they were kind enough to join me for discussion of several complex cases that don’t have clear answers and illustrate the reality that even when we know the evidence, there’s plenty of room for judgment.
Our first case is about a 63 year-old woman who has a poorly differentiated NSCLC that is just outside of the range we’d feel feasible for radiating, and it brings up issues related to trying to integrate chemo and possible radiation, the debatable role of agents like Avastin (bevacizumab) and Alimta (pemetrexed) for cancers that are hard to classify, and then how we approach managing patients who have responded well — observation or maintenance?
Here is the audio and video versions of the podcast, along with the associated transcript and figures.
rt-brahmer-riely-webinar-case-1-audio-podcast
rt-brahmer-riely-webinar-case-1-transcript
rt-brahmer-riely-webinar-case-1-figures
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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.
dr-pennell-molecular-markers-qa-audio-podcast
dr-pennell-molecular-markers-qa-transcript
dr-pennell-molecular-markers-qa-figures
Podcast: Play in new window | Download (37.8MB) | Embed
Round Table with Drs. Anne Tsao and Alex Farivar, Part 2: Mesothelioma
This is part 2 of my round table case discussion with Dr. Anne Tsao, a medical oncologist and thoracic oncology expert from MD Anderson Cancer Center in Houston, and Dr. Alex Farivar, a thoracic surgeon with expert training in mesothelioma at Swedish Cancer Institute in Seattle. This particular case covers a patient with a mesothelioma, cancer of the lining around the lung, which is also known as malignant pleural mesothelioma.
Here is the audio and video versions of the podcast, along with the transcript and figures.
round-table-with-drs-tsao-and-farivar-part-2-meso-case-audio-podcast
round-table-with-drs-tsao-and-farivar-part-2-meso-case-transcript
round-table-with-drs-tsao-and-farivar-part-2-meso-case-figures
Podcast: Play in new window | Download (46.5MB) | Embed
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