Jared Weiss, MD:We saw some really interesting data at ASCO just a few months ago from the TIGER studies. These were studies of rociletinib, a third-generationEGFRTKI that’s no longer being developed. But, all the same, we learned some interesting lessons from the biocorrelates on those studies. And so, what they did in these studies was they looked for T790M, and they looked for it in tissue, plasma, and in urine. And, these results were not always concordant. There were some patients that were positive in all three modalities, some patients for whom the test result was negative in all three modalities, some that it was found in only one, and some that it was found in any two of the three. Regardless of the way that T790M was found, the response rates were all just about the same. It was also interesting in that data set that patients who had distant metastatic spread outside of a lung, stage IVB disease, were more likely to have results found in urine or blood than patients that had intrathoracic spread only.
You cannot action a molecular change unless you find it. And so, every non-squamous case of stage IV disease deserves molecular testing. If anEGFRmutation is found, the standard of care is anEGFRTKI. There are three that are FDA approved in the United States: gefitinib, erlotinib, and afatinib. All three of these agents have been compared head-to-head against cytotoxic doublet therapy in the first-line. I think the experiment’s now been done about 14 times. And, every time, the result is pretty much the same, which is that progression-free survival is notably better with theEGFRTKI for the patient withEGFRmutation. Toxicity of the targeted therapy is lower than chemotherapy.
Erlotinib alone has been compared to erlotinib/bevacizumab in a randomized phase II Japanese trial for the treatment of metastatic stage IV,EGFR-mutated nonsmall cell lung cancer. And, the addition of bevacizumab did seem to help significantly. These results are being further evaluated in a United States trial that has recently completed accrual, and we await data on it. The addition of bevacizumab to erlotinib is not an FDA-approved option. I would consider it a controversial, but reasonable, thing to consider in clinical practice.
Gefitinib has a really interesting story. The I-PASS study, which compared gefitinib to carboplatin/paclitaxel in unselected patients, was the first to really bring out thisEGFRstory. Later subgroup analysis of that unselected trial showed us that for patients with theEGFRmutation, the TKI was much better in first-line. And, for patients without the mutation, chemotherapy was much better in the first-line. However, gefitinib lost its approval in the United States due to a failure of efficacy in unselected populations, populations without theEGFRmutation. Based on some more recent data, gefitinib has now regained its approval in the United States. And so, this question of when gefitinib should be used, again, becomes relevant. Gefitinib is a less toxic agent than erlotinib and afatinib. In particular, there is less rash and less diarrhea. For patients who want to avoid these side effects, I do consider it a preferred agent, and it is one that I use frequently in my practice.
Afatinib is a second generationEGFRtyrosine kinase inhibitor. It bindsEGFRirreversibly, unlike the first-generation agents, and then it also takes out HER2. Recent trial results have compared afatinib to first-generation TKI and showed a longer PFS. But, that longer PFS came at the expense of greater toxicity, particularly in the form of the classic side effects of rash and diarrhea. And so, I think for the very motivated patient who can tolerate that additional toxicity who’s not frail, who is more motivated to longer disease control as opposed to toxicity avoidance, afatinib can be a preferred option. We’re awaiting survival data from that trial to determine how mandatory the switch might be.
Weiss case 1:
A 65-year-old man with stage IV NSCLC.