I think I’m a few days late for the obligatory top 10 list for the year, applied to everything.  But you probably care about the top 10 for lung cancer, so here’s my list of the biggest highlights of the year.  There are certainly other appealing drugs and treatments out there, but here’s what I’d say are the issues that have changed practice or likely will (in reverse order of significance in my estimation):

10) Carbo/alimta seems to perform as well as the FDA-approved combo of cisplatin/alimta in malignant pleural mesothelioma (post here).  It’s a review of real life data from Europe and not a randomized trial, but it’s also 1700 patients, and it’s important because LOTs of patients with mesothelioma aren’t great candidates for a potentially pretty toxic drug like cisplatin.  Yes, I know pleural mesothelioma isn’t actually lung cancer, but it’s all in the chest, and the folks with mesothelioma need to have some attention from people other than asbestos lawyers.  And the platinum/alimta regimens are also going to see increasing use in lung cancer over the next several years.

9) Molecular signatures of lung tumor predict survival (posts here and here).  This work is still evolving, and there are a lot of different groups developing their own methods for predicting both the behavior of the cancer and the likelihood of response to certain treatments, but many are getting good at doing what they say they’ll do.  Still largely limited by a need for fresh tissue, and more than we routinely get for a typical biopsy in a patient with advanced disease, so it’s much more amenable to early stage NSCLC patients undergoing surgery than the broader population.  I don’t think it’s far off in the future, but it’s not likely to help people with lung cancer today. 

8) New vaccine work looks promising, leading to worldwide study as post-operative treatment in early stage NSCLC patients (post here).  Between this work using an antigen called MAGE-A3 and some other promising work with an antigen called MUC-1 (post here), this was a good year for cancer vaccines, which have historically been long on promise and appeal but short on encouraging results.  Nothing FDA approved yet, but these are now being studied in larger ongoing trials that could lead to welcome new alternatives or additions to standard chemo approaches.

7) Amrubicin looks promising as new option for recurrent SCLC (post here).  The work thus far has come out of Japan, and it’s possible that amrubicin will disappoint in larger phase III trials or just works better in Japanese patients than a North American one (as we come to appreciate real genetic differences in distinct racial populations that can be associated with different processing and tolerability of cancer treatments).   But if amrubicin is anything close to as helpful as it appears it may be from the early Japanese trials, it could become a needed additional treatment option for relapsed SCLC, potentially superior to our current primary option of topotecan.

6) Distinct subsets may benefit much more or less from erbitux in lung cancer (post here).  Ths work remains very preliminary, but if erbitux, the monoclonal antibody to EGFR, is approved by the FDA for treating advanced NSCLC (see #3, below), identifying subsets who benefit much more or less will be very helpful.  The Southwest Oncology Group has conducted some work that indicates a much more favorable result in a trial combining chemo with erbitux among those with high levels of gene expression for EGFR (called a positive FISH test, which stands for fluorescence in situ hybridization — fortunately it’s not necessary to know any details).  Erbitux is very expensive and has some problematic toxicities, so demonstrating that a limited subset of patients may have a doubling of progression-free and overall survival with erbitux compared to receiving chemo without it is very relevant.  This needs to be confirmed with further results from larger trials, but it’s an important lead.

5) We’re entering an era of tailored chemo regimens based on tumor characteristics (posts here and here).  Over the past severa decades, chemo has been one size fits all. However, we know that only a fraction of the people who receive a given chemo drug or combination receive a significant benefit.  New techniques of measuring protein or gene expression in the tumor is starting to suggest which treatments are more or less likely to be effective.  While we need new tools, approaches like these will allow us to use the tools we have most effectively.  The larger trials are just starting, but I think in the next 3-5 years we’ll be tailoring our treatments much more for patients based on measurable predictors of favorable or unfavorable response.

4) Trials show comparability of single agent chemo and EGFR tyrosine kinase inhibitor therapy (posts here and here).   Two important trials presented at the World Conference on Lung Cancer in Korea performed head to head comparisons of iressa with either taxotere as a second-line treatment for advanced NSCLC (the INTEREST trial) or navelbine as first-line chemo for elderly patients (the INVITE trials).  Both are limited by the fact that they study an EGFR inhibitor that is no longer commercially available in the US.  However, they both show that even what is likely to be an inferior EGFR oral inhibitor (at least at the dose of iressa tested, and at least in a North American population) gives the same survival as a standard chemo.  And contrary to all of our expectations, there were no subgroups based on EGFR molecular testing or clinical variables who did better with iressa.   Would tarceva fare better?  Hard to say, but right now we can say that the EGFR tyrosine kinase oral inhibitors certainly provide very similar clinical benefits as single agent chemo in these large direct comparisons.

3) A trial of first-line chemo with erbitux is positive for a significant survival benefit (post here).   Nearly four months after the press release, we don’t know anything more than that the Europe-based FLEX trial of chemo (cisplatin/navelbine) with or without the EGFR monoclonal antibody erbitux was positive, showing a significant survival benefit.  It was designed to require a benefit in the same range as Avastin (about 20-25%, I understand), so while we don’t know any of the real results, we know enough to believe that erbitux has a strong possibility of being approved by the FDA for NSCLC, and for that it may really change the landscape (but it’s hard for me to predict how without knowing more).  It pains me to think we may not receive any more details until the ASCO meeting in early June, 8 months after the press release, but that may be the sad truth.  Still, any new approval of an agent for lung cancer would be a big deal, especially if FISH testing could discriminate the big beneficiaries from everyone else (see #6, above).  Also, unlike the EGFR oral inhibitors like iressa and tarceva, which I think should never be given concurrently with standard chemo (see prior post), it appears that EGFR monoclonal antibodies can be given concurrently with standard chemo. 

2) Prophylactic cranial irradiation (PCI) significantly improves survival for responding patients with extensive SCLC (post here).  Important enough to have been pulished now in the New England Journal of Medicine (abstract here), this European study demosntrated that ED-SCLC patients with any appreciable response to first-line chemo had a huge decease in symptomatic brain metastases and a doubling of one-year survival if they received PCI, which up to now has been used quite selectively in the population of patients with ED-SCLC.  There are some legitimate criticisms of the trial, including no real definition of response and the fact that they didn’t check a brain scan before giving PCI (were they really largely running a trial of treating vs. not treating preexisting brain metastases with radiation?).  It’s not for everyone with ED-SCLC, but this trial greatly increases the motivation to offer PCI to patients with a small residual tumor burden who are still clinically doing well after first line chemo.

1) Consolidation taxotere shows no survival benefit after concurrent chemo and radiation for locally advanced NSCLC (post here).  I’d really prefer not to have the #1 most significant development in lung cancer be a negative trial result of something that doesn’t work, but the report of the trial by Hanna and colleagues from the Hoosier Oncology Group, or HOG as it’s affectionately known, pretty much rocked the lung cancer world.  Until Dr. Hanna’s presentation at ASCO this past year, about 2/3 of US oncologists (including yours truly) were giving “consolidation” taxotere chemo after concurrent chemo and radiation, based on early but very promising work from the Southwest Oncology Group (SWOG).  In a trial of just watching patients vs. giving taxotere after cisplatin/etoposide and concurrent chest radiation, survival was basically the same for both groups, even a little better for recipients of observation.  Taxotere was also associated with more side effects (which you’d expect compared with no further treatment).  This trial still has some doubters, and many oncologists are uncomfortable stopping with just two cycles of chemo (less than we’d recommend as post-operative chemo for an earlier stage patient who remains at fairly high risk after surgery).  But there’s no evidence at all that more treatment, at least with taxotere, translates to better results.  Should something else replace taxotere or should we really just stop and bite our lips waiting for a recurrence?   It’s a question I hope can be answered in a top 10 list for 2008 or 2009. 

  I’m hopeful that 2008 will give us a few new treatments and a lot of developing research for lung cancer.