Continuing on the introduction to the concept from a recent prior post, the issue of whether it’s important to see an improvement in progression-free survival (PFS) if there is no improvement in overall survival (OS) after additional therapy is going to be a central issue in lung cancer management, relevant in several key issues in coming years. This is actually a fortunate development, because it’s a by-product of there being enough valuable treatments to give sequentially that we’re questioning whether the order matters at the end of all of the treatments a patient will ultimately receive. The breast cancer community has been grappling with this issue for years, since there are a wide range of effective treatments for advanced breast cancer. Though two drug combinations have a higher response rate and PFS, that doesn’t translate to a higher OS when breast cancer patients typically receive more than four lines of treatment over time, so a typical approach is with sequential single agents rather than an urgent need to treat with the most aggressive therapy first. They also typically start with hormone therapies, which are often somewhat less active in terms of response rates and PFS but have an advantage of being associated with fewer side effects compared to standard chemotherapy.

Ten years ago it was actively debated whether there was a value in treating metastatic lung cancer, given how marginally effective and more challenging the treatments were. The concept of second line therapy really only took off around 2000-2001, when taxotere (docetaxel) was shown to improve survival, again modestly, and a challenging treatment as well. It’s really only been in the last five years, with the addition of alimta (pemetrexed) and the EGFR inhibitors iressa (gefitinib) and then tarceva (erlotinib) were introduced as additional options with activity in previously treated patients, and a side effect profile that patients and oncologists could more readily accept, that further lines of therapy became standard and anticipated. While 6-7 years ago there were almost no trials of new drugs being tested as second line treatments (alone or added to taxotere, for instance), there are now dozens of large trials of new agents being tested as second line, third line, even some fourth line options.

So we now need to struggle with the optimal order of the growing number of tools available. Is it better to use them combined early, or as single agents sequentially? And does the order matter? This issue is now at the center of our current debates.

For instance, the IPASS study (described in prior posts here and here) demonstrated convincingly that patients with EGFR mutations have a very high response rate and a very prolonged PFS, more than would be expected from standard chemo (although they also do better with chemo than patients without EGFR mutations as well). The people who believe that EGFR mutations are immensely important suggest that we absolutely MUST test for EGFR mutations before first line treatment because patients with EGFR mutations need to receive an EGFR inhibitor first line. It’s associated with major clinical benefit, to be sure (although it appeared that just about all of the patients with EGFR mutations progressed on iressa within two years). However, I’m skeptical that it’s exceptionally important (or different at all) that patients with EGFR mutations get their EGFR inhibitor first and their chemo a year later (the median PFS of patients with EGFR mutations who receive EGFR TKIs is in the range of 9-12 months) than their chemo first and their EGFR inhibitor six months later. The evidence strongly suggests that these patients will be in the exact same place 18-24 months later either way (and those higher numbers are what we now expect to see in patients with EGFR mutations).

It’s not that I don’t think it’s very reasonable to prioritize an EGFR inhibitor as an early and potentially first treatment for patients with EGFR mutations. The part that is so frustrating is that many of the same experts (including some of the most widely recognized royalty in the field) who suggest the extreme importance of testing for EGFR mutations and giving oral EGFR inhibitors first because of the PFS benefit (and no OS benefit) are the very same ones who argue that the concept of transitioning straight from first line to “maintenance” second line treatment doesn’t hold water because, while the PFS benefit is consistent and indisputable, the OS benefit isn’t quite statistically significant (see prior post). This is despite the fact that they are each extremely close to being statistically significant and that the absolute improvement in OS in the two reported phase III trials is nearly 3 months in both. This OS benefit far eclipses the benefit conferred by adding erbitux (cetuximab) to chemo for lung cancer, or the benefit with avastin (bevacizumab), for that matter. We all have a tendency to pay selective attention to the data that support our biases, and unfortunately even the biggest experts have plenty of their own biases. So we see many leaders in the field saying that PFS is more important than OS if it supports their biases, but OS is more important than PFS when they would prefer it the other way around.

We also have the AVAiL trial of cisplatin/gemcitabine with placebo or avastin that showed a significant improvement in PFS but not OS from addition of avastin (see prior post). Though PFS was the primary endpoint of the study (at least in its revised form), the lung cancer community doesn’t consider this to be a “positive” trial, at least not a resounding argument favoring the major value of avastin, since survival of the three arms differed by less than two weeks.

Where does that leave us? The evidence strongly suggests that patient survival is likely primarily a combination of the underlying biology of the cancer and the cumulative opportunity for effective treatments over time. If treatment is too aggressive too early, patients can lose performance status on the opportunity for further treatment by being harmed more than helped by the treatment – and this most certainly happens, particularly in patients who are older and/or frail but receive overly ambitious therapy better suited for healthier patients. Too light of a therapy early on and a patient can decline too much clinically from cancer progression and miss the opportunity to benefit from later therapy – the evidence for this is in the fact that the median survival in patients on the trial of immediate vs. delayed second line taxotere had exactly the same survival IF the comparison was to patients who had actually received chemo (12.5 months for both arms), but the median OS was nearly three months lower in the delayed second line treatment arm because 1/3 of the patients on that arm declined before progression was confirmed or otherwise decided not to pursue more chemo.

My take is that the goal is to get your best treatments in while a patient is well enough to tolerate them well. This doesn’t translate to a mandate of stacking all of your treatments up front, or even necessarily your best treatments. There’s an argument to be made for saving treatments for when you need them, like not blowing your best treatment if the cancer is asymptomatic and growing slowly. Under other circumstances, you may need to give your most effective/strongest treatment up front if the cancer is aggressive enough that you think you may only have one “shot on goal”.

I’m afraid that those of you who have read this far no realize that there is no single take home message here. Sorry for that, but the truth is that I really think that in most cases there are several roads to the same outcome (it doesn’t matter whether you go two blocks north and then one block east or one block east and then two blocks north). The consolation prize that oncologist and patient style and preference are very appropriate to take into account, and that this mess is all a consequence of having a bunch of effective treatments to juggle.

And would you have continued to read if I told you there wasn’t an answer right at the beginning?