For patients with an activating EGFR mutation and who develop “acquired resistance”, the pattern of progression that occurs after a sometimes long period of good initial response to an oral EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib), Iressa (gefitinib), or Gilotrif (afatanib), the evolving story of the treatment options has been a wild ride with several ups and a few downs. Over the last two years, several “third generation EGFR TKIs” with a strong affinity for EGFR activating mutations and, importantly, a different mutation called T790M, which is seen in 50-60% of patients with EGFR mutation-positive acquired resistance, but very low affinity for “wild type” (normal, non-mutated) EGFR molecules (which mediate the common, problematic side effects with EGFR TKIs, such as rash and diarrhea).  Given the very different paths that the two leading entrants – Astrazeneca’s Tagrisso (osimertinib, also previously known as AZD9291 and transiently as merelitinib) and Clovis’s rociletinib (also known as CO-1686) – it’s high time to review what has happened to get to where we are now.

The annual ASCO meeting in 2014 included very prominent presentations about these agents (Tagrisso and rociletinib, respectively), at that point still in early trials with several dozen patients each, that showed both agents had marked activity against the subset of patients with acquired resistance whose tumors test positive for T790M. At that time, AZD9291, which ultimately became osimertinib and then branded as Tagrisso, was a half-step ahead in terms of a slightly larger number of patients tested, but both agents were very promising for a population in which alternative treatment options other than standard chemotherapy. Though some concerns were raised about hyperglycemia (high blood sugar levels) in patients on CO-1686, my view at the time was that in people facing the threat of an advanced cancer, taking pills or even possibly insulin to manage blood sugar levels wasn’t likely to be a major issue if it worked effectively. Like many other lung cancer specialists and general oncologists alike, my perspective was that access to either agent would be a welcome opportunity for patients eligible for an accessible clinical trial. 

These two agents have been widely studied in a range of global trials as they continued their footrace over the next 12-18 months. In August, 2015, the remarkably early results with these two agents was featured in back to back articles (on Tagrisso and rociletinib, respectively in the prestigious New England Journal of Medicine.

But since that time, the paths of those two agents have diverged remarkably.  Tagrisso became FDA-approved in November, 2015 after continuing to demonstrate a response rate of significant tumor shrinkage in about 55-60% of T790M-positive recipients and up to 90% experiencing “disease control” that includes less significant shrinkage and stable disease. Importantly, these responses tend to last for many months to a year or longer, and this longitudinal treatment has been associated with a very low risk of significant side effects, with most patients experiencing either no issues or a rash and diarrhea that is so minimal that, in my experience, they haven’t felt warrants a hint of complaint.  The value of offering Tagrisso for T790M-positive acquired resistance has really changed the standard of care for EGFR mutation-positive patients with progression, making it instantly critical to seek and hope to find a T790M mutation, with a valuable subsequent treatment option to pursue before moving on to other options routinely offered for advanced NSCLC.

The path of rociletinib has been very dramatic over the past 6-7 months, but unfortunately it has been in a downward trajectory. Though provocative work over the past year has shown that this agent could work well in patients with T790M detected even in plasma, perhaps obviating the need for repeat tissue biopsies, the side effect profile with further use made it arguably a less attractive option than Tagrisso.  In my own experience, the constellation of nausea, diminished appetite, and diarrhea could create a cascade of weakness and misery that required aggressive dose reductions in a significant minority of patients and an occasional patient expressing dramatically “if this is what I need to do to have my cancer respond, I’d rather die” (though other patients certainly tolerate it better). But the biggest hit came in November, 2015, when the FDA reported that it was planning to delay a decision on potential approval of rociletinib after updated information revealed that the response rate reported to rociletinib of 59% was actually an “unconfirmed” response rate that dropped to about half that rate when looking only at confirmed responses (though the latest published update pegs response rate at 45%). The fortunes for rociletinib, along with Clovis’s stock price, dropped like a rock.

 Since then, clinical trials with rociletinib have continued on, and the FDA has continued its review process for the drug. The Oncology Drug Advisory Committee (ODAC) to the FDA, eviewing the evidence in April, came back with a 12-1 vote against approval until results from a randomized trial of rociletinib vs. chemotherapy be completed and demonstrate a clear benefit for rociletinib.  Then, in early May, Clovis announced very suddenly that the FDA, which almost always followed ODAC’s thoughtful recommendations, had notified the company that the FDA would not be offering an approval until further data supported its use. In that same press release, Clovis announced that it was terminating all trials with rociletinib (and was laying off 35% of its employees).

One important issue that the potential approval of rociletinib raised was the question of whether it should be compared to osimertinib or not. Technically, rociletinib didn’t need to be better than its predecessor to the market in the same space, but it is hard to determine what value there is in offering an agent with seemingly less activity and worse side effects than an agent we already have available. This issue of a strong incumbent will be a critical factor for other would-be challengers, further behind in development, which enter a world with Tagrisso as an entrenched, effective therapy in this setting, so how might other agents fit in?

A key relevant question here is how similar or dissimilar these agents truly are. One might well assume that there is a great deal of “cross-resistance” to drugs in the same family, as we see minimal activity of one first or second generation EGFR TKI after another (such as trying Tarceva after Iressa, or Gilotrif after Tarceva), just as you wouldn’t expect to have many people wildly excited about having a Pepsi after drinking a two liter bottle of Coke. But in fact, Dr. Lecia Sequist and colleagues from Massachusetts General Hospital recently reported that they have seen several cases of tumor shrinkage or prolonged stable disease on Tagrisso – including in the brain as well as other parts of the body -- in patients who had demonstrated clear progression on rociletinib previously. As someone who had patients progressing on rociletinib in clinical trials, I followed this lead and have treated several of my patients with Tagrisso and also seen several very encouraging responses after progression on rociletinib. This is an important finding for patients in this setting who may benefit.

These advances are very significant, but we must still acknowledge the work that still needs to be done. Third generation EGFR TKIs may prove to offer meaningful benefits to the 40-50% of patients with T790M-negative acquired resistance, or we may need to search for better options elsewhere. It will also represent a great breakthrough if we can do repeat biopsies to check for T790M or other mutations in circulating plasma of patients rather than be required to pursue invasive biopsies at several time points over the course of treatment.  Though we probably can’t predict future developments much better than we might have predicted the drama in this space over the past two years, I can predict that it will be eventful and that we will only have a better understanding of and treatments for EGFR mutation-positive NSCLC in the future.

What do you think of these developments?