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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Continuing with Dr. Ross Camidge as our focus (see yesterday’s post for a brief update from him on the afatinib/cetuximab trial), today let’s turn to the recent webinar program he and Dr. Ben Solomon did with us on the subject of ALK Inhibition: From Biology to FDA-Approved Therapy for Advanced NSCLC”.   After Dr. Solomon provided an excellent summary of the biology and early clinical experience with XALKORI (crizotinib) that was so impressive in (the admittedly limited population of) ALK-positive patients, Dr. Camidge led us through the second part of the program.  His focus was on the practical implications from here: with a newly approved therapy of XALKORI tied to a rather uncommon molecular marker, who should we be screening for it?  And what are the options for these patients after they develop acquired resistance to XALKORI?

Here is the presentation by Dr. Camidge in audio and video podcast format, along with the associated transcript and figures for the program:

dr-camidge-on-molecular-screening-and-postcriz-rx-audio-podcast

dr-camidge-on-molecular-screening-and-postcriz-rx-transcript

dr-camidge-on-molecular-screening-and-postcriz-rx-figures

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Several weeks ago, we were fortunate enough to be joined by not one but two international stars in lung cancer research that is being translated directly from lab bench to bedside of the patient.  I don’t think there’s a more clear and inspiring example of good science leading to effective therapy, albeit for a limited patient population, than the story of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib (recently FDA approved and commercially launched as XALKORI) for patients with an EML4-ALK rearrangement (approximately 4% of the broader NSCLC population).  Drs. Ben Solomon from Peter MacCallum Cancer Centre in Melbourne, Australia, and Ross Camidge from University of Colorado, in Denver, collaborated with a handful of other international researchers from all over the world to study crizotinib and conduct the critical trials, shepherding its development into a treatment now available to help a targeted subset of patients with this targeted therapy.

Dr. Ben Solomon spoke first, providing an overview of the (short) history of the EML4-ALK translocation and how crizotinib began to be studied in the first patients.  He then took us on a tour of the highlights of both the efficacy data for this new agent and the side effect profile.  Here’s the audio and video podcast versions of his presentation, along with pdf files of the accompanying transcript and figures:

dr-solomon-alk-inhibition-science-to-approved-therapy-audio-podcast

dr-solomon-alk-inhibition-science-to-approved-therapy-transcript

dr-solomon-alk-inhibition-science-to-approved-therapy-figures

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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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The marker known as an anaplastic lymphoma kinase (ALK) translocation has been all over the lung cancer news in recent weeks, most notably in the setting of being the marker in about 4% of patients with non-small cell lung cancer (NSCLC) that is correlated with a high probability of response to the ALK inhibitor crizotinib, which was just approved by the FDA for patients whose tumors demonstrate this marker on a test in a central reference laboratory.  But this marker may also be correlated with responsiveness to Alimta (pemetrexed), providing a readily available treatment option before or after these patients start crizotinib.

If this sounds familiar, it’s because I actually described such an association of particular benefit in ALK-positive NSCLC with Alimta back in February, when our friend, Dr. Ross Camidge, from the University of Colorado, published a retrospective review of patient outcomes with Alimta at the University of Colorado. They evaluated the outcomes of 89 patients tested for an EGFR mutation, KRAS mutation, or ALK translocation and also found that the median progression-free survival of their 19 ALK positive patients was significantly higher, at 9.0 months, than that seen in 37 who were wild type (WT, or “no mutation) for all three markers (4.0 months), and that neither patients with EGFR nor KRAS mutations demonstrated a significant difference compared with triple negative patients.

Though Dr. Camidge and I both noted that these results can only be taken so far, as a retrospective analysis from a single institution, these conclusions were corroborated by a remarkably similar retrospective review that comes out of Korea by Lee and colleagues, who evaluated 95 patients with advanced NSCLC and who had received Alimta as a second line or later therapy between March, 2007 and April, 2010. Specifically, they assessed outcomes as a function of whether these patients had an EGFR mutation (N = 43, or 45%), an ALK translocation (N = 15, or 16%), or WT for both (N = 37, or 39%), finding that patients with an ALK translocation had a more favorable outcome with Alimta across several endpoints.  These included a significantly higher objective response rate compared to those with an EGFR mutation or WT for both (47% vs. 5% and 16%, respectively; p = 0.001), as well as disease control rate (87% vs. 26% and 57%, respectively; p < 0.001) and median time to progression (TTP) (9.2 vs. 1.5 and 2.8 months, respectively; p = 0.001).

(click on image to enlarge)

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A new article just coming out in the Journal of Clinical Oncology by our friend Dr. Ross Camidge and colleagues from the University of Colorado suggests that patients who have an ALK rearrangement appear to often have a particularly long progression-free survival (PFS) with Alimta (pemetrexed).  Though it comes from a single institution and is the first time such an idea is being presented, it’s a very interesting report.

The University of Colorado is on the very short list of cancer centers that are more or less routinely ordering EGFR and KRAS mutation testing, as well as looking for an ALK rearrangement, in the vast majority of their patients with NSCLC.  Last year, Dr. Camidge mentioned to me that he and colleagues were noticing that many of their patients who were found to have an ALK rearrangement also seemed to do unusually well with Alimta, so they reviewed their center’s experience to assess this more carefully.  Specifically, they retrospectively reviewed the clinical results for 89 of their patients who had received Alimta with or without another chemotherapy and who had also been tested for these three mutations.  They then reviewed the PFS of patients on an Alimta-containing regimen depending on whether patients had an EGFR mutation, KRAS mutation, ALK rearrangement, or was “triple negative”.

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In the last decade, the treatment of NSCLC has evolved very significantly, and one of the leading ways has been that we’ve gone from having no established role for treatment after initial, first line therapy to having multiple agents with a proven benefit.

It’s worth clarifying that as maintenance therapy is increasingly being considered as an option after first line therapy, a distinction between this and second line therapy. Maintenance therapy is given to prolong the period before someone who has achieved a response or stable disease on first line treatment demonstrates progression for the first time, while second line therapy is the term more commonly reserved for treatment after someone has demonstrated evidence of progression for the first time after first line therapy.

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The historic standard for advanced NSCLC up until a few years ago was for patients to complete 4-6 cycles of platinum-based doublet chemo, and then for patients who were doing well and had responded or demonstrated stable disease to take a break from treatment and be followed until progression. At that point, many patients would re-initiate chemo or targeted therapy with an oral agent like Tarceva (erlotinib).

Part of the premise was that ongoing treatment with challenging chemotherapy generally led to cumulative side effects, and at the same time, the limited work that had been done on fixed duration vs. ongoing chemotherapy until progression failed to show a significant improvement in survival with prolonged chemo, though it was associated with increased side effects.

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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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