Patients with EGFR
mutant lung cancer have a unique clinical course, even after development of acquired resistance to EGFR TKIs. No additional EGFR targeted therapies have been conclusively shown to be effective in this setting. Treatment options include participation in a clinical trial or standard cytotoxic chemotherapy with or without EGFR TKI continuation. Here we show that local therapy with surgery, radiation, or radiofrequency ablation in selected patients is associated with a median overall survival of 41 months, a median time to progression of 10 months, and a median time to next systemic therapy of 22 months. These remarkable outcomes in patients with EGFR
mutant lung cancer are likely a result of multiple factors including the unique clinical course of this disease, patient selection, continued benefits of the TKI even after progression18,20,35,36
, and potential benefits of local therapy.
Patients with EGFR
-mutant lung cancers have improved outcomes with the use of EGFR TKI therapy, but also have better results with chemotherapy and better surgical outcomes as well7,37
. Even with the development of acquired resistance, patients with EGFR
mutant lung cancers have superior survival with a median survival after EGFR TKI progression of 16 months38
compared to a median overall survival from diagnosis of 12 months for patients with advanced NSCLCs not selected by EGFR
. Among patients with acquired resistance, outcomes vary, however, one analysis suggests that the emergence of the T790M point mutation is associated with improved post progression outcomes38
Our data demonstrate that, in selected patients with acquired resistance, local therapy can lead to longer progression free intervals that appear to be superior to the responses historically seen with standard treatment options and can be done safely with minimal toxicities. The outcomes in patients who received local therapy may reflect in part the more indolent natural history of patients with limited sites of disease. In this cohort, the median time from diagnosis of advanced disease to local therapy was 26 months, indicating a more indolent disease course that predates any local therapy intervention. There were no other differences with a cohort of patients with EGFR mutant lung cancers and acquired resistance who did not receive local therapy to suggest other factors useful for patient selection. Important differences between the two groups may not be apparent do to the small number of patients who received local therapy in our series.
While the patients reported here had long median overall survivals and time to progressions, there was a wide range of outcomes. Outcomes appeared to best when the site of local therapy was the only known site of disease. Two patients progressed within 5 months with brain metastases and two other patients with shorter progression free intervals had bone metastases at the time of local therapy. We suggest CNS imaging prior to any considered local therapy and avoiding local therapy in the setting of bone metastases unless the bone lesions are treated and stable over a prolonged period of time. In addition to analysis of clinical and molecular characteristics, site of progression and rate of tumor growth, similar to PSA velocity40
, may be helpful to identify patients most likely to have good outcomes after local therapy. Genomic analysis of growing metastatic sites compared to stable metastatic sites and/or the primary tumor may also provide useful information that may allow us to appropriately tailor the use of local therapy to patients who will derive the most benefit41,42
There are several caveats in interpreting our data. Local therapies were only employed in 10% of individuals with tumors with EGFR TKI acquired resistance, clearly a selected group of individuals. Almost all patients in this cohort continued erlotinib or gefitinib after local therapy. It is likely that this contributed to their favorable clinical outcomes as well. Prospective, multicenter evaluation of local therapy is needed to more clearly define the patient population that may benefit from this treatment strategy.
There is currently no consensus on the optimal management of patients whose tumors develop acquired resistance to EGFR TKIs. Our standard approach to treatment of EGFR
mutant lung cancer with acquired resistance to EGFR TKI therapy is based upon burden of disease (especially the number and location of metastatic sites) and patient symptoms (see ). If a patient has asymptomatic, indolent progression of disease on EGFR TKI, our practice is to continue erlotinib or gefitinib and to watch the patient for the development of clinical symptoms or an acceleration of disease progression. Despite progression on TKI therapy, there is data both in the laboratory18
and the clinic to suggest that the continuation of EGFR therapy is beneficial. All aspects of this treatment algorithm would benefit from prospective study. With the potential benefit of learning about a small cell histologic transformation as well as the prognostic value of EGFR T790M, we biopsy patients at the time of development of acquired resistance as part of routine care.
An Approach to Management of Patients with Acquired Resistance to EGFR TKI therapy
In this series, we show that local therapy for oligometastatic disease can be a useful treatment option for patients with acquired resistance to EGFR TKI therapy. EGFR- mutant lung cancer typically has a more indolent natural history compared to EGFR wild-type disease, and a subset of EGFR mutant patients with oligometastatic disease may benefit from locally directed therapies. In these patients, local therapy leads to long progression free survival, overall survival and, with continued EGFR inhibition, prolonged time until a change in systemic therapy is required. These local therapies can usually be performed with minimal toxicity and result in months to years of disease control. Prior to proceeding with local therapy, patients should have a full extent of disease evaluation. Our experience suggests local therapy should be considered for patients with oligometastatic lung cancer with acquired resistance to EGFR TKI.