Geoffrey R. Oxnard, MD
Plasma genotyping can, in most cases, identify T790M-positivity in non-small cell lung cancer (NSCLC), which gives patients the option of receiving the targeted therapy osimertinib (Tagrisso) without the need for a tumor biopsy, according Geoffrey R. Oxnard, MD, at the 2016 European Lung Cancer Conference (ELCC).
The analysis investigated the effectiveness of osimertinib in 216 pretreated patients with NSCLC with acquired resistance to first-line EGFR inhibitors who had both both plasma and tumor genotyping results from the phase I AURA trial.1
Of the 179 patients who tested positive for T790M in the tumor, the overall response rate (ORR) was 62% and the median progression-free survival (PFS) rate of 9.7 months. In the 167 patients who tested positive for T790M in plasma, results were similarly positive, with a 63% ORR and an 8.2-month median PFS.
However, outcomes were unexpectedly favorable in 104 patients who tested negative by plasma for T790M, with a 46% ORR and an 8.2-month PFS. This was compared with 58 patients who tested negative for T790M in the tumor who exhibited a 26% ORR and 3.4-month PFS.
To better understand how plasma genotyping may change the use of osimertinib and the significance of some tumors testing positive for T790M in the plasma, but not in the tumor, OncLive
interviewed Oxnard, assistant professor of medicine, Harvard Medical School, Dana-Farber Cancer Institute, who presented the analysis at ELCC.
OncLive: What were the goals of the study?
Patients develop resistance to an EGFR inhibitor, and at that moment we have a decision to make. Do we start chemotherapy, or do we put them through a biopsy to try to characterize their resistance and use that information to guide their treatment? If the biopsy shows T790M, we can give them osimertinib, and they could have a dramatic response and a durable PFS with little toxicity. However, to do this we are currently required to do a biopsy. So the question we asked in this study was, can we use a blood test, and in which situations can it be used for T790M resistance genotyping?
What were the most significant findings?
We performed an analysis of hundreds of patients treated on the phase I AURA trial of osimertinib. We looked back at their tumor results and their plasma results. We found out that the plasma genotyping, which used a technology called beaming, a digital pCR technology, could detect about 60% to 80% of the EGFR-mutations in the plasma. It could not detect all cases; some cases just don’t have any DNA. When it is positive for a sensitizing mutation, it can be believed. The specificity is very high. Interestingly, when it is positive for a T790M mutation the specificity is more modest. About 30% of the plasma-positives did not have a T790M-positive tumor; there was a disconnect between the plasma result and the tumor result.
How did that play out in the outcome? The response rate of patients receiving osimertinib with a positive T790M in their tumor was high—over 60% and they had a long PFS. The response was similarly high in the plasma-positive patients. Those who had a T790M mutation in their plasma had a great response rate and long PFS. It looks like plasma can be used to identity patients who can benefit from this drug, and a simple blood test can be used to to decide who should get the drug instead of needing to go through the biopsy.
The catch is the negatives. With T790M-negative in a tumor it means a low response rate in the range of 20% with a short median PFS. Those patients don’t benefit from osimertinib and they should get chemotherapy. That is part of our standard approach now. However, if the plasma is negative for T790M, that includes some true negatives and some false negatives. There were some cases were the blood test missed T790M. Those patients who were plasma-negative but tumor-positive still had a reasonable response rate in the range of over 40%, and a median PFS of 8-plus months. Those patients need a biopsy. A biopsy can tell us which of those plasma-negatives are in fact tumor-positive and should get osimertinib, and which are in fact tumor-negative and should get chemotherapy.
What are the biggest advantages of avoiding a biopsy?
With the approval of osimertinib in Europe, the United States, and Japan, it is now standard to perform a biopsy, when feasible, for T790M, and doing that makes patients candidates for osimertinib. But it’s not feasible for all patients. A biopsy involves risk and some tumors are not obtainable by a biopsy. Bone lesions and brain lesions, for example are difficult to biopsy, and therefore not all patients can get a biopsy. That means that some patients cannot capitalize on this new drug. A liquid biopsy gives patients who can’t get a biopsy the opportunity to receive osimertinib, and it’s much quicker and easier than a tumor biopsy.