One of the longstanding ideas in lung cancer management is that you exhaust the benefit of first line combination chemotherapy after 4-6 cycles of treatment.  This is based on a few trials that showed no survival benefit for treating beyond that point, as summarized in this early post I wrote all the way back in my first few months of doing this (OncTalk days, pre-GRACE).  This standard of care is based in part on the premise that the incremental adverse effects may escalate faster than any incremental benefit for a platinum-based doublet.  With cisplatin, cumulative nausea, fatigue, risk of significant kidney damage, neurotoxicity, and overall “platinum blues” tend to make treatment beyond 6 cycles infeasible and disproportionate to any potential added benefits of ongoing therapy.  With carboplatin, cumulative cytopenias (low blood cell counts) and a rapidly escalating risk of a severe and potentially dangerous hypersensitivity reaction (which can also occur with ongoing cisplatin but is notorious and almost inevitable with carboplatin) make indefinite carboplatin too challenging and inadvisable.

In the last few years, the concept of maintenance therapy for patients who haven’t experienced progression or prohibitive side effects after 4-6 cycles of first line combination chemotherapy has taken hold.  Initially, this default strategy was baked into the development of Avastin (bevacizumab): the trial that led to approval of Avastin gave six cycles of carbo/Taxol (paclitaxel)/Avastin, followed by maintenance Avastin.  It showed a survival benefit for the whole program, but it was not possible to say whether the benefit was from the addition of Avastin with chemo, from the maintenance Avastin, or both components.

Meanwhile, many trials over the last few years have shown a clear improvement in progression-free survival (PFS) and a suggestion of improvement in overall survival (OS) with addition of switch maintenance therapy, where a new treatment is initiated after 4-6 cycles of first line combination chemotherapy is completed in non-progressing patients.   This work is discussed in more detail elsewhere and led to a general standard of at least considering maintenance therapy in this setting for appropriate patients, even if the data supporting a survival benefit are flawed enough to leave most experts considering maintenance therapy far from a mandate.

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A few months ago I wrote about the preliminary reported results from the AVAPERL trial, which started patients with previously untreated  advanced nonsquamous NSCLC up to four cycles of cisplatin/Alimta (pemetrexed)/Avastin (bevacizumab), then randomized patients who hadn’t progressed after four cycles to either maintenance Alimta/Avastin or Avastin alone.  At the European Society for Medical Oncology (ESMO) 2011 meeting, the investigators (Barlesi and colleagues) presented early results that showed a very significant improvement in progression-free survival (PFS) from the beginning of all treatment, at 10.2 vs. 6.6 months (HR 0.50, p < 0.001).  For those of you who understand things better visually, here’s the curve plotting the PFS outcome for the two different groups, with a very impressive difference:

(click on image to enlarge)

The same results, plotted from the time of randomization to combination vs. single agent Avastin as maintenance therapy, are even more striking:

I didn’t have any information about overall survival (OS) back in September, but here’s the preliminary OS results, with numbers from the time of starting all treatment:

So while these are only preliminary results, the difference of a 25% better OS with continuation of Alimta is impressive to me, especially considering that the arm with the worse outcome, receiving maintenance Avastin alone, has a median survival of nearly 16 months, which we would consider to be quite excellent compared the outcome of other advanced NSCLC trials (12 months for cisplatin/Alimta on one large phase III randomized trial, 12 months with carboplatin/Taxol (paclitaxel) with Avastin in another).  So the inferior arm on AVAPERL has still done very well: the superior arm is just doing meaningfully better.

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I’m at Swedish Hospital, not in Stockholm, Sweden now, where the European Multidisciplinary Cancer Congress is going on.  But there, the preliminary results of the AVAPERL phase III randomized trial were just reported, and they certainly look encouraging for the combination of Alimta (pemetrexed) and Avastin (bevacizumab) as a maintenance therapy for patients with Avastin-eligible advanced NSCLC who hadn’t progressed after four cycles of cisplatin/Alimta/Avastin, compared with maintenance Avastin alone.

(click on image to enlarge)

As I mentioned, I don’t have all of the details from the presentation, really just the press release, which at least conveys some highlights.  As shown above, a total of 362 patients who hadn’t progressed after first line chemo/Avastin were randomized to either of the two maintenance therapy arms, and the combination arm showed a significantly longer progression-free survival (PFS) counting from the beginning of all treatment, at 10.2 vs. 6.6 months (HR 0.50, p < 0.001), but also a numeric result for PFS that far exceeded the numbers we’ve seen from other first line trials, where PFS has generally been in the 5-7 month range.  There were no unexpected safety issues, but otherwise, I don’t have other details.

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Here’s the second talk from our recent webinar, partnering with LUNGevity Foundation to cover the ASCO Highlights in Lung Cancer, and this talk followed after the presentation by Dr. Mary Pinder on highlights in SCLC, early stage NSCLC, and mesothelioma and covered developments in advanced NSCLC.   Dr. Nasser Hanna, an international leader in the field from Indiana University, summarized the most important new data in this arena.

Below you’ll find links to the audio and video versions of the podcast, as well as the transcript and figures from his talk.

hanna-asco-2011-highlights-advanced-nsclc-audio-podcast

hanna-asco-2011-highlights-advanced-nsclc-transcript

hanna-asco-2011-highlights-advanced-nsclc-figures

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   The third and final part of my conversation with Drs. Tom Hensing from North Shore Health System in Chicago and David Jackman from Dana Farber Cancer Institute in Boston covered a presentation of an Asian never-smoking woman with an advanced lung adenocarcinoma, the demographic picture most closely associated with potentially but not necessarily having an EGFR mutation or ALK rearrangement.

   We cover the question of whether, in someone with a significant probability of one of these particular molecular markers, it’s worth obtaining tissue and delaying treatment to tailor treatment on the basis of these results.  We also discuss the range of options for maintenance therapy in someone who has many alternatives for continuing one or more agents from the first line setting or switching to a new treatment.  Finally, we turn to the question of managing treatment for a patient who has a prolonged response to an EGFR inhibitor and then develops an acquired resistance to that therapy.

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   The second part of my conversation with Drs. Tom Hensing from North Shore Health System in Chicago and David Jackman from Dana Farber Cancer Institute in Boston covered a case of a relatively young, generally healthy woman diagnosed with a lung adenocarcinoma that turned out to be stage IV.  

   Here, we discuss our priorities for molecular testing and how the results of EGFR, KRAS, and EML4-ALK testing would alter our clinical recommendations.  We then discuss the options for this patient, with special focus on how long to continue first line therapy and when and how to transition off of first line treatment into either observation or maintenance therapy.

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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.

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A lot of new data have emerged over the last 2-3 years that have addressed the concept of “maintenance therapy” for patients with advanced NSCLC (see Dr. Socinski’s excellent podcast for a general review).  The basic idea is that a patient is treated with first line chemo-based treatment, with or without the angiogenesis in inhibitor Avastin (bevacizumab), and the fortunate majority have some degree of tumor shrinkage or at least stable disease.  The degree of benefit from each subsequent cycle of chemotherapy tends to decrease with further treatments, so you reach a point of diminishing returns for an often-challenging two or three-drug combination.  While the well-established standard up until a few years ago had been to stop first line therapy and observe a patient for progression before initiating second line treatment, several trials in the last few years have demonstrated that lighter ongoing maintenance therapy, more to suppress the cancer at its current state of prior response and non-progression than to markedly shrink the cancer further, provides a very significant improvement in progression-free survival, and a less clear but at least strongly suggested overall survival benefit (the trials showing a significant improvement in overall survival have some substantial flaws).

There are two basic concepts of maintenance therapy: one is switch maintenance therapy, in which someone stops all of the first line drugs and switches to a new therapy to maintain the response.  It has the theoretical advantage of treating the cancer from a new angle, with an agent that the remaining cancer has not had the opportunity to develop resistance to.  The approvals of both Alimta (pemetrexed) and Tarceva (erlotinib) as maintenance therapies are based on this concept.  In contrast, continuation maintenance therapy is when one or more of the agents from the first line setting is continued after a fixed number of cycles of first line therapy.  We haven’t had much data on this concept with modern chemo approaches, but this year at ASCO, a couple of interesting trials were presented that provided some additional insight on this approach (though oncologists often use this approach with Avastin and Alimta, we haven’t seen data that demonstrate continuation maintenance with these agents is beneficial).

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We learned several months ago that the ATLAS trial of maintenance Avastin (bevacizumab) with either Tarceva (erlotinib) or placebo did not demonstrate a significant improvement in overall survival (OS) with Tarceva, despite the fact that it was associated with an improvement in progression-free survival (PFS).  This is in contrast with the similar trial called SATURN that randomized advanced NSCLC patients after first line chemo to maintenance Tarceva vs. placebo, but without the Avastin during and after first line chemo, as SATURN demonstrated a significant improvement in OS along with a significant improvement in PFS.

In Dr. Mark Socinski’s great overview of the topic of maintenance therapy, he noted these discrepant results, with no obvious explanation.  We received additional information about the OS results at ASCO, where it was reported that at the latest time point of analysis, in July of 2009, the median OS was 15.9 months vs. 13.9 months, favoring the addition of Tarceva.  This corresponded with a hazard ratio of 0.90, or 10% improvement, over the entire course of treatment, a result that was not statistically significant.  The overall survival curves are shown below:

(click on image to enlarge)

Admittedly, it doesn’t look like a major separation, but there is a modest advantage with the combination.  You can decide whether that’s a glass half empty or half full.

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Dr. Mark Socinski, international leader in the field of lung cancer, from the University of North Carolina at Chapel Hill, gave a terrific presentation on timing and selection of treatment after the first line setting for advanced NSCLC.  In addition to the podcast of his presentation itself, here now is the question and answer session that followed it.

The Q&A portion includes slides with the questions as well as some slides that illustrate key points.  Below, you’ll find the audio and video versions of the podcast, the figures, and also the transcript of the program.

socinski-qa-session-maintenance-therapy-audio-podcast

socinski-qa-session-maintenance-therapy-figures

socinski-qa-session-maintenance-therapy-transcript

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