Journal of Thoracic Oncology:
Local Ablative Therapy of Oligoprogressive Disease Prolongs Disease Control by Tyrosine Kinase Inhibitors in Oncogene-Addicted Non–Small-Cell Lung Cancer
Weickhardt, Andrew J. MBBS, DmedSc*; Scheier, Benjamin MD*; Burke, Joseph Malachy MD*; Gan, Gregory MD‡; Lu, Xian MSc‡; Bunn, Paul A. Jr. MD*; Aisner, Dara L. MD, PhD§; Gaspar, Laurie E. MD, MBA‡; Kavanagh, Brian D. MD, MPH‡; Doebele, Robert C. MD, PhD*; Camidge, D. Ross MD, PhD*
*Department of Medicine, Division of Medical Oncology, †Department of Radiation Oncology, University of Colorado Cancer Center, Colorado; ‡Department of Biostatistics and Informatics, Colorado School of Public Health and University of Colorado, Colorado; and §Department of Pathology, University of Colorado Cancer Center, Colorado.
Disclosure: Drs. Weickhardt, Doeble, and Camidge have received speaking honoraria from Pfizer. The other authors declare no conflicts of interest.
Address for Correspondence: Andrew J. Weickhardt, MBBS, DmedSc, University of Colorado Cancer Center, Aurora, CO 80045. E-mail: firstname.lastname@example.org
Introduction: Many patients with oncogene-driven non–small-cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors experience limited sites of disease progression. This study investigated retrospectively the benefits of local ablative therapy (LAT) to central nervous system (CNS) and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively.
Methods: Patients with metastatic ALK+ NSCLC treated with crizotinib (n = 38) and EGFR-MT NSCLC treated with erlotinib (n = 27) were identified at a single institution. Initial response to the respective kinase inhibitors, median progression-free survival (PFS1), and site of first progression were recorded. A subset of patients with either nonleptomeningeal CNS and/or four sites or fewer of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same tyrosine kinase inhibitors. The subsequent median progression-free survival from the time of first progression (PFS2) and pattern of progression were recorded.
Results: Median progression-free survival in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. Twenty-five of 51 patients (49%) who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, one with surgery) and continuation of the same targeted therapy. Post-LAT, 19 of 25 patients progressed again, with median PFS2 of 6.2 months.
Discussion: Oncogene-addicted NSCLC with CNS and/or limited systemic disease progression (oligoprogressive disease) on relevant targeted therapies is often suitable for LAT and continuation of the targeted agent, and is associated with more than 6 months of additional disease control.
Patients with metastatic non–small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase gene rearrangements (ALK+) or epidermal growth factor receptor-mutations (EGFR-MTs) have high response rates and long progression-free survival times when treated with crizotinib or EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, respectively.1–6 However, progression inevitably occurs because of either inadequate central nervous system (CNS) penetration of the drug in some cases of CNS progression, or biological change in the tumor such as the development of new kinase domain mutations in the drug target or the development of alternate oncogenic drivers.7–16
Although studies of many novel agents are ongoing, there are no currently approved targeted therapies specific for treatment of such patients upon progression. Although continuation of the TKI therapy by itself with no local therapy to slow the progression or continuation of the TKI in combination with chemotherapy have been advocated as options for these patients,17–20 the current standard therapeutic option at the time of progression is to treat the patient with cytotoxic chemotherapy alone. Local therapies, such as radiotherapy or surgery, have had little role outside symptom palliation in this setting. However, radiation therapy of isolated CNS progression in patients with EGFR-mutant NSCLC being treated with EGFR-TKIs and continued systemic administration of the TKI if there is no evidence of systemic progression has recently been described.21 Such an approach relies on the logic that CNS progression could reflect inadequate drug penetration rather than a change in the biology of the cancer. Therefore, the patient is unlikely to have developed systemic resistance to the drug and may be deriving significant ongoing benefit from its use.
Building on this logic, the approach we describe here uses local therapies to ablate sites of oligoprogressive disease that occurs systemically, as well as in the CNS, and continuing the same targeted therapy and is based on two underlying hypotheses. First, given our increasing knowledge about the different mechanisms of acquired resistance to TKIs in EGFR-MT and ALK+ disease, we hypothesized that any biological change mediating acquired resistance occurs as a stochastic clonal event that favors survival in accordance with Darwinian evolutionary principles.14–16 Consequently, if treated with ablative therapy before widespread dissemination of the resistant clone, disease control may be prolonged until either a new event occurs or resistant clones that have disseminated expand enough to become detectable. Second, we hypothesized that there is ongoing benefit from the targeted therapy in other sites of (nonprogressing) disease because of continuing suppression of sensitive clones that have not yet developed acquired resistance. Consistent with this, patients with EGFR-MT disease who progress often experience a disease flare when the EGFR-TKI is discontinued,22 and rechallenge of these patients with the same EGFR-TKI after only a short time off therapy can lead to re-responses.23,24 In addition, treatment beyond progression of EGFR-MT NSCLC with an EGFR-TKI has been associated with improved overall survival, compared with those in whom the TKI was permanently discontinued.25 Analogous benefits of the continuation of trastuzumab beyond progression have been well described in metastatic breast cancer.26–29
This study describes a single-institution experience of using local ablative therapy (LAT) and continuation of the same targeted therapy to treat ALK+ and EGFR-MT metastatic NSCLC patients who progress either within the CNS and/or at limited systemic sites (oligoprogressive disease) while on crizotinib or erlotinib, respectively. In most cases we used stereotactic body radiation therapy (SBRT) as our LAT of choice. SBRT has previously been shown to be highly effective in achieving local control in a variety of organs, without significant toxicity.30–37
MATERIALS AND METHODS
Patients eligible for inclusion in this retrospective analysis included all patients with histologically confirmed ALK+ or EGFR-MT metastatic NSCLC at the University of Colorado Cancer Center treated with crizotinib, or erlotinib between May 2005 and December 2011 with adequate follow-up data. Patients were identified through a query of the Colorado Molecular Correlates database for ALK+ patients determined by break-apart fluorescent in situ hybridization assay or EGFR mutation positive patients (exon 19 deletions or exon 21 L858R mutations) determined either through direct sequencing or allele-specific polymerase chain reaction assays. An institutional review board approved protocol permits clinical correlates to be made on all patients seen at the University of Colorado in whom molecular analyses have been conducted within the Colorado Molecular Correlates laboratory.
Baseline clinical characteristics were determined by retrospective collection from electronic records, including age at diagnosis (taken at date of diagnostic biopsy), sex, tumor histology, prior therapy, method of CNS imaging before initiation with erlotinib or crizotinib, date of diagnosis of any known CNS involvement, treatment of any known CNS involvement before the initiation of erlotinib or crizotinib, smoking status, and sites of metastatic disease. If patients did not have imaging of the CNS within 3 months before commencing TKI therapy and had no previous history of CNS metastases, they were assessed as having unknown CNS status. Smoking status was categorized as current (smoked within less than a year before start of therapy), former (quit more than a year before start of therapy), or never (less than a 100 lifetime cigarettes).
All ALK+ patients received crizotinib (Xalkori, Pfizer, La Jolla, CA) starting at 250 mg twice a day on either the phase I expansion cohort of PROFILE 100138 or the nonrandomized phase II PROFILE 1005 clinical trial,39 and received staging every 8 weeks (PROFILE 1001), or every 6 weeks (PROFILE 1005) with computer tomography (CT) or positron emission tomography (PET)/CT. Imaging of the brain at either baseline or on treatment in these trials was not mandatory for any patient but was performed at investigator discretion. All EGFR-MT patients received erlotinib (Tarceva, Astellas, Farmingdale, NY) starting at 150 mg once a day, with two of 27 receiving erlotinib in combination with the insulin-like growth factor-1 receptor monoclonal antibody cixutumumab (Imclone, New York, NY) as part of a clinical trial.40,41
Baseline and ongoing CNS and body imaging with magnetic resonance imaging (MRI), CT and/or PET/CT for the 25 of 27 EGFR-MT patients treated off study was performed according to investigator discretion. The two EGFR-mutated NSCLC patients treated with erlotinib and cixutumumab on trial had interval body CT scans performed every 6 weeks while on study, although both withdrew from study after 7 and 8 months before progression to continue erlotinib alone, and had staging performed from this time according to investigator discretion. Median progression-free survival (PFS1) was calculated from time of initiation of targeted therapy to first progression of disease (as per Response Evaluation Criteria in Solid Tumors version 1.1 ) or clinical progression (as assessed by clinician), or death from any cause (using Kaplan–Meier methods). Sites of first progression (CNS or external to the CNS [eCNS]) were documented.
On the basis of institutional practice, patients who progressed on their oral targeted therapy who had either leptomeningeal disease, more than four sites of eCNS progression, poor performance status (Eastern Cooperative Oncology Group >2) or poor tolerance of their targeted therapy were not considered suitable for LAT (n=26). A subset of patients with progression after initial treatment with either crizotinib or erlotinib with either nonleptomeningeal CNS progression and/or less than 4 sites of eCNS progression, adequate performance status (Eastern Cooperative Oncology Group <2), and good tolerance of their targeted therapy (n = 25) were considered for LAT to the site(s) of progression and continuation of the same oral targeted therapy. Before LAT, patients underwent a biopsy of the site of their progressive disease to determine the molecular mechanism of resistance to targeted therapy if this was determined to be safe by their treating oncologist and interventional radiologist which, in part, have been reported separately.16 Patients were instructed to withhold their oral targeted therapy on the days of local therapy with radiation and restart on the day after radiation was completed, with no change in dosage. Those patients who received surgical LAT were instructed to withhold the TKI until the surgical team considered it appropriate to recommence oral dosing.
The characteristics and timing of local ablative therapy (SBRT, standard radiation therapy [XRT], stereotactic radiosurgery [SRS], whole brain radiation therapy [WBRT] or surgery), and number of disease sites treated was recorded. Electronic records of patients who received radiation or surgery were reviewed for evidence of relevant systemic or local toxicity related to the volume irradiated for 6 months from the end of the LAT, including but not limited to fatigue and headaches after CNS irradiation; pneumonitis after lung irradiation; radiation-induced liver disease after liver irradiation; and skin toxicity after any SBRT or XRT. PFS2 was measured from the time of first progression until second progression on the same targeted therapy, using Response Evaluation Criteria in Solid Tumors 1.1 or death from any cause. Data analysis was performed up to January 1, 2012.
Statistical analysis for creation of Kaplan–Meier curves was performed using Prism V software (Graphpad, San Diego, CA). Median survival time, confidence intervals, and a multivariate analysis with a Cox proportional hazards model was performed using version 9.3 of SAS/STAT software (SAS institute Inc., Cary, NC).
Thirty-eight ALK+ patients received crizotinib, 28 (74%) of whom had progressed at the time of analysis. Twenty-seven EGFR-MT patients received erlotinib, 23 (85%) of whom had progressed at the time of analysis. Patient characteristics are summarized in Table 1. The majority of patients (63 of 65, 97%) had adenocarcinoma histology, and the median age was 58 years. Collectively, 19 of 65 patients (29%) had known CNS metastases before commencement with targeted therapy, but 29 of 65 patients (45%) with no history of CNS metastases did not have MRI or CT imaging of their brain performed in the 3 months before commencement on either drug. The median duration of follow-up was 20 months. The PFS1 of the 65 NSCLC patients treated with either crizotinib or erlotinib was 10.3 months (9.0 months for ALK+ patients, 13.8 months for EGFR-MT patients [Table 1]).
Among 28 ALK+ patients who had progressed at the time of the analysis, 13 (46%) first progressed in the CNS at PFS1 (two of whom progressed simultaneously in the CNS and eCNS) and the CNS failure rate was similar in the 18 ALK+ patients who had a documented CNS status (14 with CNS metastases, four with no CNS metastases) before commencing crizotinib (seven of 18, 39%). Among EGFR-MT patients, five of 23 patients (22%) first progressed in the CNS at PFS1 (two simultaneously in CNS and eCNS), and again the CNS failure rate was similar in the subgroup of 10 EGFR-MT patients who had a documented CNS status (five with CNS metastases, five with no CNS metastases) before commencing erlotinib (two of 10, 20%).
Of the 28 ALK+ patients who had progressed, 15 of 28 (54%) received LAT after first progression and were treated beyond progression with crizotinib. Of the 23 EGFR-MT patients who had progressed, 10 (43.5%) received LAT after first progression and were treated beyond progression with erlotinib. Overall, 25 of 51 patients (49%) received LAT at first progression. All patients who received LAT recommenced their TKI after therapy. The median time from PFS1 to the start of LAT was 3.7 weeks. The PFS1 was 9.8 months for all 25 patients with oligoprogressive disease, who received LAT and continuation of targeted therapy (9.0 months for ALK+ patients, 12.0 months for EGFR-MT patients). The PFS1 was 12.8 months for all patients with progression, who did not receive LAT and continuation of targeted therapy (7.2 months for ALK+ patients, 13.9 months for EGFR-MT patients Table 1).
The pattern of progression at PFS1 for those 25 patients treated with LAT for oligoprogressive disease is shown in Table 2. Seventeen of the 25 patients (68%) had restaging of their CNS with an MRI of the brain at the time of PFS1. Seventeen of the 25 patients (68%) had systemic restaging with PET/CT at the time of PFS1, with all others using CT scanning. Thirteen patients (nine ALK+, four EGFR-MT) first progressed in the CNS, with 10 of 13 patients (77%) only having progression in their CNS while still having control of systemic disease outside the CNS. All six patients with fewer than four CNS metastases were treated with SRS. A single patient with eight sites of cerebral metastases was treated with SRS to each site at an outside institution. Otherwise, all other patients with four or more CNS metastases received WBRT. The majority of the 15 patients who progressed outside the CNS and were treated with local therapy were treated with SBRT (15–54 Gy, median 40 Gy), with eight of 15 (53%) having a single site of progression treated. Up to four eCNS sites were treated (median 2), with the most common sites being bone and lung. One patient underwent an adrenalectomy, and two patients were treated with XRT to bone metastases (either with 20 Gy in five fractions or 30 Gy in 10 fractions).
For the 17 patients who received CNS restaging at PFS1, the median interval of CNS restaging between PFS1 and PFS2 was 3.1 months. The median interval of systemic restaging between PFS1 and PFS2 was 2.1 months. The median follow-up post-LAT at the time of analysis was 9.4 months. For the 25 patients who received LAT and continued on targeted therapy, the median PFS2 from the time of PFS1 was 6.2 months (Table 3, Fig. 1). The median PFS2 in patients with initial CNS only progression was 7.1 months. Median PFS2 in patients with initial eCNS progression, including three patients who had CNS progression detected within a month of systemic progression, was 4.0 months. The pattern of progression at PFS2 is shown in Table 3. Of patients who progressed initially in the CNS, 50% next progressed outside the CNS. Similarly, of patients who progressed initially outside the CNS, 53% next progressed outside the CNS again. At the time of analysis, six of 25 patients (24%) had not progressed again after local therapy post-PFS1 after a median follow-up of 7 months. There was a trend for patients whose time to first progression was less than or equal to 12 months to have a shorter time to second progression, (hazard ratio=3.45, 95% confidence intervals 0.92–12.99, p = 0.067) but this was not statistically significant.
The majority of adverse events relating to ablative therapy occurred in patients having WBRT. Radiation-induced liver damage was not observed in the patient who received liver SBRT. Grade 3 fatigue was reported in two patients within the 6 months after WBRT, but there were no other documented grade 3/4 adverse events attributable to radiotherapy (Table 4).
Oncologists have traditionally discontinued or changed systemic therapy when there is objective evidence of radiological or clinical progression, intolerable toxicity, or completion of a fixed number of treatment cycles. However, in cases of progression on a previously beneficial targeted agent for molecularly subtyped cancer other options may exist. Specifically, our experience suggests that when patients with EGFR-MT or ALK+ NSCLC progress on erlotinib or crizotinib, respectively, and the progression occurs in only a limited number of sites (oligoprogressive disease) it may be reasonable to consider LAT to the sites of progression and continuation of the TKI (Table 5, Fig. 2). Forty-nine percent of patients treated with either erlotinib or crizotinib who progressed at our institution were deemed appropriate for this treatment strategy.
Patients treated with crizotinib or erlotinib in this series had a median PFS1 of 10.3 months, consistent with literature precedent.1–6 Although retrospective series of radiotherapy used in oligometastatic disease at diagnosis in metastatic NSCLC report good local control rates and better overall survival than in historical controls,42–48 there is little published data about the use of local therapy for oligoprogressive disease on therapy. This study suggests that in patients with EGFR-MT or ALK+ NSCLC on erlotinib or crizotinib therapy who develop either less than four systemic progressive lesions (the maximum treated in this series) and/or CNS progression, LAT (either radiation or surgery) and continuation of the TKI may extend disease control by over 6 months. Our results expand on recently published work on the role of LAT in patients with EGFR-MT. A Japanese group reported a median eCNS PFS2 of 5.6 months after LAT of isolated CNS progression in 17 NSCLC patients who had achieved at least stable disease for more than 6 months on an EGFR-TKI,21 and an American group reported a median PFS2 of 10 months in 18 NSCLC patients with EGFR-MT after LAT of isolated sites of eCNS progression.49
In our series, no patients receiving LAT had radiological evidence of leptomeningeal disease, which is associated with poor outcomes, lack of clear effective therapy, and therefore unlikely to be suited to a local treatment approach.50 Strikingly, nearly half (13 of 28, 46%) of all ALK+ patients progressed first in the CNS, with the majority (11 of 13) 85% still responding or with stable disease systemically, making a LAT approach combined with ongoing use of crizotinib particularly attractive within this group. In patients without baseline CNS imaging with documented CNS progression, it is not possible to categorically state whether new CNS lesions reflect true CNS progression or simply the new discovery of lesions that preexisted. However, the fact that the rates of CNS progression were very similar among those with known CNS status at baseline (39%), suggests that the predominant effect is one of true CNS progression. Failure in the CNS may be because of inadequate crizotinib exposures rather than a change in the dominant biology of the tumor.10,51–53 Similar data relating to the potential for the CNS to represent a relative sanctuary site with respect to EGFR-TKI therapy for EGFR-MT disease also exist.10 In contrast, systemic mechanisms of resistance to these drugs relate to several different biological changes in the tumor, such as kinase domain mutations in the target enzyme or the development of additional oncogenic drivers.13,15,54–56 It is uncertain whether the potential for there to be different explanations for failure in CNS and systemic sites accounts for a trend toward improved PFS2 in patients receiving LAT for isolated CNS progression at PFS1 relative to those patients receiving LAT for systemic progression. In our series, patients with isolated CNS progression had a median time to next progression of over 7 months, as compared with a PFS2 of 4.0 months in patients who experienced first progression outside the CNS; however, this difference was not statistically significant (hazard ratio for progression 0.85, 95% confidence interval 0.29–2.47,p = 0.76).
There are several limitations of this study. Safety data on radiation-related side effects within this study were collected and graded retrospectively. However, the safety of combining aggressive, ablative-intent SRS or SBRT regiments with TKI- or monoclonal antibody-based EGFR inhibition has been reported for both CNS and extracranial sites, so the apparent good tolerability of our approach would not be unexpected.57–60
There was a lack of standardized timing interval in systemic restaging patients taking erlotinib although not on clinical trial, and no standardized timing of CNS staging in either the crizotinib or erlotinib group. The median interval of restaging between PFS1 and PFS2 was 3.1 months for CNS in those with restaging MRI at PFS1, and 2.1 months for eCNS sites of disease, which is less than half the time interval of the additional apparent disease control from LAT. On the basis of institutional precedent, we limited the number of eCNS lesions considered for LAT to four or fewer sites, and in most cases the number of CNS lesions considered for SRS as opposed to WBRT to less than four. Emerging data suggest that SRS alone might be appropriate for a higher number of brain metastases as long as the total burden of tumor is limited,61 and there would be an opportunity to avoid the neurocognitive toxicity associated with WBRT.62 Similarly, whether the treatment of symptomatic and asymptomatic CNS metastases is equally beneficial to the patient remains unknown. All patients who received LAT continued to receive their TKI post-LAT, therefore, although we can comment on the outcomes associated with the combined approach, we cannot distinguish the specific contribution of each element.
Perhaps most importantly, we do not have a comparator group to judge the true benefit of our LAT/TKI continuation approach. Historical controls of other chemotherapies in NSCLC cannot accurately be used given that this was a retrospective review of a molecularly defined population, treated across several different lines of therapy. Of note, as the PFS1 in the LAT-treated group and the non-LAT–treated group were comparable (10.3 versus 12.8 months), we do not seem to have preselected a more indolent population for LAT within this study. Although we have estimated the time to the next progression event in the LAT-treated group, additional LAT at the time of second progression was considered in several cases when only further oligoprogressive disease was manifested (data not shown). Consequently, in any prospective evaluation, comparing this approach, for example, to some standard chemotherapy in a defined line of treatment, both the clear delineation of the criteria for considering the initial and any repeat LAT acceptable and an assessment of the benefit of the approach on overall survival and quality of life and not just the PFS before the next intervention may be most informative. Within this study, at the time of analysis only four of 25 of the LAT group and 10 of 26 of the non-LAT–treated progressive group had died and therefore overall survival data are not mature.
Despite these limitations, this study provides rationale for considering the approach of LAT and continuation of a relevant well-tolerated TKI in the treatment of oligoprogressive EGFR-MT and ALK+ NSCLC as an alternative to switching systemic therapy (Table 5, Fig. 2). However, we would strongly advocate that to delineate the true extent of benefit, a prospective clinical trial is required across multiple centers with defined treatment criteria and standardized restaging technology (PET/MRI) should be used at defined intervals to minimize bias.
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EGFR-mutant non–small-cell lung cancer; anaplastic lymphoma kinase gene arrangement non–small-cell lung cancer; Radiation therapy; Oligoprogressive disease
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