SBRT for oligoprogressive oncogene addicted NSCLC

Lung Cancer 106 (2017) 50–57

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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan

Review

SBRT for oligoprogressive oncogene addicted NSCLC L. Basler ∗ , S.G.C. Kroeze, M. Guckenberger Department of Radiation Oncology, University Hospital Zurich, Rämistrasse 100, CH 8091 Zurich, Switzerland

a r t i c l e

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Article history: Received 9 December 2016 Accepted 5 February 2017 Keywords: Stereotactic body radiotherapy (SBRT) Oligoprogressive disease (OPD) Oncogene addicted lung cancer Resistance to targeted therapy Tyrosine kinase inhibitors EGFR mutation

a b s t r a c t Lung cancer is one of the leading causes of cancer death in men and women and treatment outcome continues to lag behind other common cancer types. A subset of lung adenocarcinoma patients exhibit a somatic mutation in EGFR or an ALK rearrangement. In these patients, targeted TKI therapy results in higher response rates, improved PFS and reduced side effects compared with platinum-based chemotherapy. Despite initial activity of the TKIs, ultimately all patients present with disease progression after about a year on TKI therapy due to resistance development. About 15–47% of patients present with limited oligoprogressive disease (OPD): such patients show only a limited number of metastases with progression in radiological imaging. Radical local treatment to all oligoprogressive lesions is thought to eradicate the de-differentiated clones and restore overall sensitivity of the metastatic disease. Retrospective studies suggest that aggressive local treatment using stereotactic body radiotherapy (SBRT), surgery or others can be used to eradicate TKI-resistant subpopulations enabling prolonged TKI treatment “beyond progression”, which may lead to increased PFS and overall survival. This review focuses on the biological background of resistance development, systemic and local treatment options with a focus on SBRT, as well as challenges in defining the state of OPD and current clinical studies in oligoprogressive oncogene addicted NSCLC. © 2017 Elsevier B.V. All rights reserved.

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Oncogene addicted NSCLC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 2.1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 2.2. Resistance to oncogene targeted therapies and second-line therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 2.2.1. EGFR drug target alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 2.2.2. EGFR bypass track activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 2.2.3. ALK drug target alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 2.2.4. ALK bypass track activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Oligoprogressive disease (OPD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 3.1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 3.2. Oligoprogression of oncogene addicted NSCLC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 3.3. Treatment options of oligoprogressive disease: systemic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 3.3.1. Early switch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 3.3.2. Treatment beyond progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 3.4. Treatment options of oligoprogressive disease: local therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 3.4.1. Surgical treatment of oligometastatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 3.4.2. SBRT for the treatment of oligometastatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 3.5. Toxicity of concurrent TKI treatment and SBRT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Outline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 4.1. Defining the state of OPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 4.2. Biomarkers and liquid biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

∗ Corresponding author. E-mail address: [email protected] (L. Basler). http://dx.doi.org/10.1016/j.lungcan.2017.02.007 0169-5002/© 2017 Elsevier B.V. All rights reserved.

L. Basler et al. / Lung Cancer 106 (2017) 50–57

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4.3. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

1. Introduction Lung cancer is one of the leading causes of cancer death in men and women. In 2012 lung cancer was diagnosed in 1.8 million people and resulted in 1.6 million cancer deaths world wide [1]. Non-small cell lung cancer (NSCLC) is the most common lung cancer type and accounts for 85% of patients while small cell lung cancer (SCLC) incidence has decreased over the past two decades [2]. Around two thirds of NSCLC patients present with inoperable Stage IV and one third already shows advanced metastatic disease at the time of diagnosis. The 5-year survival rate in the United States is 17% [3] and progress in improving the outcome has lagged behind other common cancer types for many decades. 2. Oncogene addicted NSCLC 2.1. Definition In the past decade common somatic driver oncogene mutations were identified such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) as well as less common MET, ROS1, BRAF and other mutations. Their identification led to the development of targeted therapies using tyrosine kinase inhibitors (TKIs), which completely changed the systemic treatment of these subpopulations of patients with mutation positve, advanced NSCLC. Approximately 10–20% of Caucasian and 30–40% of Asian NSCLC adenocarcinoma patients exhibit a somatic mutation in EGFR, with an additional 4–7% of patients having an ALK rearrangement. The frequency is higher in never smokers, women and patients of East Asian ethnicity [4]. In these molecularly defined populations, targeted therapy using TKIs has produced higher response rates (RR), improved progression free survival (PFS), better tolerability with reduced side effects and superior quality of life (QoL) compared with standard platinum-based chemotherapy, which has been shown in several randomized trials [5]. 2.2. Resistance to oncogene targeted therapies and second-line therapy Despite initial activity of the TKIs, acquired resistance eventually develops with median PFS of 8–10 months in patients with ALK rearrangements and 9–13 months in patients with EGFR mutations and ultimately all patients develop progressive disease [6–10]. This acquired resistance can be attributed to a number of common mechanisms in the majority of cases, although reasons remain unknown in ∼35% of cases [11–13]. A rebiopsy with molecular analysis should be performed in patients with acquired resistance to TKIs in order to identify the molecular mechanism of resistance. If it is not feasible to perform a rebiopsy a liquid biopsy represents a new method for tumor genotyping and should be considered at the time of progression [14]. 2.2.1. EGFR drug target alterations The most common acquired resistance against first generation TKIs involves the development of a second EGFR mutation, T790 M, which can be found in 49–60% of resistant patients and leads to a change in the ATP-binding pocket of EGFR with increased affinity for ATP and consecutive reduced affinity for reversible TKIs (e.g.

erlotinib or gefitinib) by competitive inhibition or steric hindrance [15–18]. This discovery led to the development of third-generation TKIs, e.g. osimertinib, which bind to EGFR in an irreversible way and render the reduced affinity irrelevant. These new drugs represent the treatment of choice in these cases [19,20]. 2.2.2. EGFR bypass track activation Another way of developing a resistance against treatment with TKIs is the activation of bypass tracks. Examples for this are MET amplification (5%), HER2 amplification (8–13%), BRAF- (1%), EMT(1–2%) and PIK3CA-singaling (1%), as well as transition to SCLC (10%) [13,18,21,22]. Multiple clinical trials investigating the inhibition of these bypass tracks are currently running with mixed results [23]. 2.2.3. ALK drug target alterations ALK amplification (6–16%) and several ALK mutations (22–33%) have been discovered. Compared to the common T790M mutation as mechanism of acquired resistance in EGFR mutated patients there appears to be no dominant additional ALK mutation, which renders targeting of these secondary mutations quite difficult [23]. Additionally the concentration of crizotinib in the cerebrospinal fluid is negligible [24] which limits its potential in patients with brain metastases. Ceritinib is a second-generation TKI which, compared to crizotinib, offers a higher ALK selectivity and subsequently 20 times higher potency and increased CSF penetration but does not inhibit the MET kinase [25–27]. Two phase I studies were able to show a benefit of ceritinib in patients with crizotinib resistance with an ORR of 56% and PFS of 6.9 months [28]. In Japan the second generation ALK inhibitor alectinib is approved for all patients with advanced NSCLC and ALK-rearrangement and demonstrated superiority compared to crizotinib as a first-line treatment in a randomized phase III trial [29]. Other second-generation ALK inhibitors are in development mainly focusing on increased CSF penetration and broader activity against secondary ALK mutations [30]. 2.2.4. ALK bypass track activation Similar to acquired resistance in EGFR-mutated patients, bypass track activation is an important mechanism of resistance in ALKrearranged patients with possible increase of EGFR signaling (30–35%), KIT amplification (10%) or other changes in driver mutations (5%) [18]. 3. Oligoprogressive disease (OPD) 3.1. Definition The concept of oligometastatic disease was first described in 1995 by Hellman and Weichselbaum as an intermediate state between a localized and systemic disease [31]. Agressive local treament to all oligo-metastatic lesions is considered as a curative apporach in this concept, which is supported by observations from irradiation and resection of lung and liver metastases: in patients with colorectal carcinoma or sarcoma [32–35] long-term overall survival is achieved in about 20–25% of the patients. Similar data on better-than-expected survival after local treatment of oligometastatic diease is available for NSCLC as well [36–38].

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Oligoprogresion needs to be differentiated from oligometastasis. In the oligo-progressive concept, patients may have had widespread systemtic diease initially, but after systemic treatment with a partial or complete response, only a limited number of metastases show progression in radiological imaging. Local treatment to all oligoprogressive lesions is thought to eradicate the de-differentiated clones and restore overall sensitivity of the metastatic disease. For patients without a driver mutation treated with chemotherapy, a pattern-of-failure analysis in patients after first-line systemic therapy demonstrated that local recurrence is the predominant site of failure suggesting that aggressive local treatment using SBRT could improve PFS in a significant proportion of patients [39]. Common metastatic sites of wild-type NSCLC include lung, adrenal, bone and brain metastases. Doebele et al. were recently able to show that patients with different driver oncogenes show differences in patterns of metastatic spread [40]. Oncogene addicted tumours have an increased likelihood of developing liver metastases (EGFR and ALK mutant) and pleural or pericardial metastases (ALK mutant). However, the most common site of failure is still the lung itself (66%). 3.2. Oligoprogression of oncogene addicted NSCLC While the concept of OPD implies a potential benefit of local treatment in this intermediate state of disease, the question arises whether this state actually exists in NSCLC [41]. Data from published literature indicates that the proportion of patients progressing with an oligo-progressive pattern of disease ranges from 15 to 47% during EGFR TKI treatment [42–44]. The OPD concept is further supported by data from re-biopsy series, where sites of progression due to TKI resistance are selected in a Darwinian manner and contribute to systemic re-seeding with new sites of distant disease and subsequent widespread disease progression [22,43,45]. A pattern of failure analysis of EGFR-mutated NSCLC patients to identify candidates for ablative SBRT showed that the majority of treatment failures was located in the primary tumor site (47%), combined local and distant failure frequency was 32.6%, while distant failure was the least common site with 20.4%. The most significant predictor of local failure was primary tumor size (p = 0.004). Patients with local failure had a shorter PFS (11.8 months) compared to patients with distant failure (14.9 months) [45]. The results support the idea of disease progression due to the development of TKI-resistant clones at the primary tumor site with subsequent distant progression. Another study with 104 EGFR-mutated NSCLC patients with progression under erlotinib or gefitinib showed only limited oligoprogression with isolated CNS progression in 16% and solitary extracranial lesions in 23% of patients [44]. A recent review of TKI treated patients at The Royal Marsden demonstrated that 11 out of 30 (37%) patients had OPD suitable for SBRT [46]. 3.3. Treatment options of oligoprogressive disease: systemic therapy Due to the only recent recognition of the oligoprogressive state, there are currently no evidence-based treatment recommendations available. Both local, systemic and combined-modality treatment options are possible and are currently under evaluation. Additionally, it may become true that there is no homogeneous oligo-metastatic patient cohort but that patient-indivdual treatment will be adapted to other factors such as detailed mutational status, availability of next-line systemic treatment options, number and location of oligo-progressive lesions, local symptoms due of metastases, dynamic and imaging characteristics of disease progression.

Systemic treatment options following disease oligoprogression on a TKI are either to switch the systemic agent at the point of radiological progression or to continue the TKI until clinical progression. 3.3.1. Early switch Switch of systemic therapy at the first sign of radiological progression is possible to a next-generation TKI (e.g. afatinib after first-line gefitinib) or cytotoxic chemotherapy if no further targeted treatment is available. Conventional cancer treatment algorithms also know the discontinuation of the current therapy at the time of progression [18]. Oncogene-addicted cancers however present a different situation with possible rapid flare and hyperprogression after termination of TKI treatment. In a study of the Memorial Sloan Kettering group with 61 EGFR-mutated NSCLC patients who developed TKI resistance, 14 (23%) developed rapid disease flares after discontinuation of TKI treatment with subsequent hospitalization or death after a median of 8 days [47]. An explanation for this effect is that dormant subpopulations of the tumor that were supresssed by the original TKI start to grow rapidly after TKI discontinuation [48]. 3.3.2. Treatment beyond progression Current clinical data suggest that continuation of TKI beyond radiological progression might lead to increased PFS. Besides the previously mentioned rapid disease progression after TKI discontinuation, another reason is that at the point of switching systemic therapy, further targeted therapy options are limited or non-existent and response rates to salvage chemotherapy are low. If next-line targeted therapy options are available, as-late-aspossible switch to the next line of treatment might prolong the overall response duration [49,50]. The phase II ASPIRATION study with 208 patients could demonstrate increased PFS with continuation of first-line erlotinib beyond radiological progression. PFS1 of the ITT population was 10.8 months, while PFS1 and PFS2 for the treatment beyond PD were 11.0 months and 14.1 months respectively [51]. There is however data suggesting that contiuation of TKI beyond wird-spread progression does not show a benefit in combination with a platinum-based chemotherapy [52], as well as permetrexed or docetaxel. There was no significant difference in PFS but an increased frequency of grade 3 and above toxicity for the combined treatment [53]. 3.4. Treatment options of oligoprogressive disease: local therapy According to the current ESMO [14] as well as NCCN guidelines, local treatment involving radiotherapy or surgery is recommended in stage IV NSCLC for local palliation or symptom control of metastases with or without spinal cord compression, superior vena cava syndrome, painful neural or soft tissue invasion, haemoptysis, as well as symptomatic airway obstruction. The treatment of brain metastases without driver mutations should be based on the prognosis of the patient, which can be estimated based on the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) [54,55]. Additionally both guidelines mention the possibility of a combined local treatment with continuation of first-line TKI in the setting of OPD as a reasonable treatment option with possible improved PFS or even long-term survival. The NCCN guidelines explicitly emphasize the use of definitve radiotherapy, particularly SBRT in these settings if it can be safely delivered. 3.4.1. Surgical treatment of oligometastatic disease Surgery in an oligometastatic setting is considered to be a standard practice in the treatment of liver and lung metastases from colorectal cancer with improved local control and overall survival,

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Fig. 1. Oligoprogressive disease and treatment options. The natural course of disease progression involves local resistance development in patients with TKI sensitive disease under TKI treatment. This leads to radiological oligoprogression with an option to continue the TKI treatment beyond progression. Ultimately all patients develop systemic TKI resistance which results in systemic chemotherapy, immunotherapy or switch to next-generation TKIs as remaining options. Local irradiation with concurrent TKI treatment is able to eradicate oligoresistant disease to restore TKI sensitivity, subsequently prolonging overall TKI treatment time.

though this has not been confirmed in a randomized trial for ethical reasons [56]. In advanced stage IV NSCLC the possibilities of surgery are often limited, though indications for solitary, especially brain and adrenal metastases, as well as local palliation do exist [14,35,57,58].

3.4.2. SBRT for the treatment of oligometastatic disease Stereotactic body radiotherapy (SBRT) is an advanced radiotherapy technique that has been shown to achieve very high local tumor control rates (>90%) with very low toxicity and can be used to non-invasively ablate sites of oligometastases and oligoprogressive disease (Fig. 1). There is support for the concept of local therapy for sites of OPD in mutation positive NSCLC patients from two small US single-center restrospective series. In a retrospective study of the Memorial Sloan Kettering group with a total of 184 patients, a series of 18 EGFR-mutated patients with TKI therapy received local therapy for extra-cranial OPD followed by continuation of TKI. Local

therapy was defined as surgery, radiotherapy or RFA. The median PFS after local therapy was 10 months, median time to change in systemic therapy was 22 months and OS was 41 months [42]. The University of Colorado group reported a retrospective series of 65 patients with TKI treatment of either crizotinib or erlotinib who presented with progression in the CNS and/or limited extracranial oligoprogression [43]. 51 of the patients had progressed at the time of analysis out of which 25 (49%) were deemed suitable to local therapy. Median PFS1 of all patients (n = 65) was 10.3 months, while ALK-mutated patients (n = 38) had a shorter PFS1 of 9.0 months compared to 13.8 months in EGFR-mutated patients (n = 27). Patients with CNS progression (n = 10) received local treatment with either SRS (<4 lesions) or WBRT (>4 lesions) and showed a median PFS1 of 10.9 months and PFS2 of 7.1 months. 20% (n = 2) of these patients did not progress after local treatment, 30% (n = 3) progressed in the CNS and 50% (n = 5) showed extracranial progression. Patients with extracranial oligoprogression (n = 15) were

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Table 1 Prospective clinical trials involving aggressive local treatment in the setting of targeted therapy and oligoprogressive disease (OPD). Trial

Tumor entity

Criteria

Study design

Intervention

Primary outcome

NCT02019576

Renal Cell Carcinoma

Single arm phase II, multi-center

SBRT

Local control

NCT01941654

NSCLC (EGFR mutated)

Single arm phase II

SBRT

PFS at 1 year

NCT01573702

NSCLC (EGFR mutated)

Single arm phase II

SBRT or other local ablation followed by Erlotinib

PFS

NCT02450591

NSCLC (EGFR mutated)

Single arm pilot study

SBRT, surgery or other local ablation to all remaining sites of disease

Feasibility

NCT01796288

NSCLC (EGFR mutated)

Randomized phase II

RT to all gross tumor sites + Erlotinib vs. Erlotinib alone

PFS

HALT

NSCLC (EGFR/ALK mutated)

Oligoprogression in patients receiving 1st line Sunitinib therapy 1st line TKI treatment for at least 3 months with CT-confirmed good partial response. ≤ 4 PET-positive residual tumor sites Oligoprogression in patients following EGFR-TKI treatment. ≤5 OPD sites (intra and extra-cranial) Completion of 12 weeks Erlotinib treatment. ≤5 disease sites at time of diagnosis, all amenable to definitive local therapy. 12 weeks of second-line Erlotinib without disease progression. ≤5 disease sites Confirmed response to TKI therapy after a treatment time of 2–3 months. ≤3 OPD sites (extra-cranial), all suitable for treatment with SBRT

Randomized phase II/III, multi-center

SBRT in addition to TKI therapy vs. TKI therapy alone

PFS

treated with SBRT in most cases with a single case of adrenal metastectomy mentioned. PFS1 and 2 in these patients were 9.0 and 4.0 months, respectively. 27% (n = 4) of these patients showed no signs of progression after local treatment, 20% (n = 3) progressed in the CNS and 53% (n = 8) showed further extracranial progression. As a second study with 38 patients, ALK fusion positive patients developing extra-cranial OPD (n = 14) under treatment with crizotinib were treated with local SBRT or hypofractionated radiotherapy [59]. Local contral rates were 100% (6 months) and 86% (12 months) while single fraction equivalent doses (SFED) above 25 Gy showed 100% 12-month local control vs. 60% with doses less than 25 Gy single fraction equivalent. SFED is the dose delivered in one fraction, which causes the same biological effect as another fractionation scheme [60]. There was no sign of acute or late grade >2 toxicity. Radiotherapy increased the median overall time on crizotinib to 28 months compared to 10.1 months in patients who did not receive local treatment. Overall survival in patients continuing treatment with crizotinib for >12 months was 72% vs. 12% (<12 months; p = 0.0001). Median PFS1 for patients receiving local ablative treatment was 14 months compared to 7.2 months in patients who were not eligible to receive local treatment (widespread systemic disease, poor Karnofsky Performance Status, or OPD) and switched to alternative systemic therapy. Median PFS2 was 5.5 months and was longer in patients with 1–2 lesions (7 months) compared to 3–4 lesions (2 months; p = 0.12). However the absence of randomisation limits interpretation of these studies. A randomized study with an appropriate control group is therefore required in order to effectively evaluate the true benefit of adding SBRT to TKI therapy in patients with OPD [14,35,56]. 3.5. Toxicity of concurrent TKI treatment and SBRT We were able to identify five studies with 81 patients in total, receiving concurrent treatment with EGFR-inhibitors (gefitinib, erlotinib) and stereotactic radiotherapy to different anatomical

sites, mainly originating from NSCLC [43,61–64]. Concomitant treatment with stereotactic radiotherapy and gefitinib in recurrent glioma, as well as in NSCLC brain metastases showed no severe toxicities. In a study of stage IV NSCLC patients by Wang et al. involving combined gefitinib and SBRT to a maximum of three lung metastases, grade 3 toxicity was observed in 29% of patients (4/14) possibly due to concurrent treatment. Symptoms consisted of esophagitis, stomatitis and radiation-induced pneumonitis [65]. In a prospective study by Iyengar et al. with combined treatment of extra-cranial NSCLC metastases using erlotinib and SBRT, 29 events of severe toxicity could be observed in 24 patients, 4 of which could be attributed to SBRT. 12 deaths were observed with no discernable relation to concurrent therapy [61]. For ALK-inhibitors there is less data availabe and only two retrospective studies with combined crizotinib and SBRT with a total of 29 patients could be found. In both studies the treatment with crizotinib was paused during SBRT and no severe tocivities could be observed [43,59]. In summary, concurrent extracranial SBRT and TKI treatment may be associated with a moderately increased risk of toxicity in the irradiated volume but there are no signs of increased toxicity in the setting of cranial stereotactic radiotherapy. 4. Outline 4.1. Defining the state of OPD There are several uncertainties in defining the state of OPD in patients and distinguishing it from widespread systemic disease progression. While patients with OPD may benefit from aggressive local therapy, patients with advanced metastatic disease might have no additional advantage. Current factors to differentiate between both states are the number of metastatic lesions as well as anatomical site. Advances in diagnostic radiology involving functional imaging (e.g. PET-CT/MRI, diffusion-weighted MRI or dynamic contrast-enhanced ultrasonography) have greatly increased our ability to detect metastases with a high sensitiv-

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ity, as well as evaluating treatment response and distinguishing between tumor response, progression and more recently defined states of pseudoprogression or hyperprogession. The combination of functional imaging and next-generation MR-Linac image-guided radiotherapy with the possibility of daily treatment evaluation shows great potential and might be the next step in this direction. 4.2. Biomarkers and liquid biopsy While these advanced diagnostics improved our capabilities by a large margin, the definition of biological markers to distinguish between these differing tumor states and OPD is still under clinical development. As previously stated, in patients with acquired resistance to TKI a rebiopsy should be performed to determine the biological background of the resistance. If there is no feasible option to perform a rebiopsy, a liquid biopsy should be considered. In the future liquid biopsies may not only help us in analyzing the treatment response or failure but may also be used to predict the clinical benefit of adding SBRT in the setting of OPD. One promising scenario is the used of liquid biopsy testing for T790M in oligoprogressive patients treated with first-line EGFR targeting TKIs. Systemic treatment after local ablation of the oligoprogressive metastases could then by guided by repaeated liquid biopsy: if the patient becomes negative for T790M, continuation of the first-line TKI would appear reasonable but a switch to e.g. Osimertinib would be performed in patients remaining positive for T790M. In addition to the local effect of SBRT on TKI resistant sub-clones in oligo-progressive lesions, the potential ‘abscopal effect’ of high dose per fraction radiation on the patient’s immune system is considered one of the mechanisms of potential clinical benefit [66–69]. Liquid biopsies to analyze circulating tumor DNA (ctDNA), as well as tumor tissue, where available, offer an opportunity to prospectively assess neo-antigen burden in relation to clinical outcome.

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A single arm phase I trial (NCT02450591) in the USA is assessing the addition of local therapy following 12 weeks of Erlotinib in newly diagnosed EGFR mutation positive patients who present with oligometastatic disease with all disease sites amenable to local therapy. The primarly endpoint is the feasibility of 5 patients completing local therapy to all sites of disease. HALT is a randomized, multi-center, phase II/III study, which is currently in preparation as an intergroup trial between CR-UK and EORTC. In contrast to the trials above, HALT will provide a direct assessment of the benefit of providing SBRT in addition to TKI therapy in patients with oligo-progressive mutation positive NSCLC. Patients will be randomized (2:1) to receive SBRT in addition to background TKI therapy (experimental group) or TKI therapy alone (control group). The purpose of HALT is to determine how well and how safely SBRT can destroy those NSCLC lesions which are no longer being controlled by TKI and to assess how much longer such an approach will allow patients to obtain clinical benefit from TKI treatment compared with continuation of TKI alone. 5. Conclusion Acquired resistance to TKI represents a major challenge in the treatment of oncogene addicted lung cancer, ultimately all patients present with disease progression after about a year on TKI therapy. The concept of oligoprogression supports the idea of disease progression due to the development of TKI-resistant clones with subsequent distant progression. Retrospective studies suggest that aggressive local treatment using SBRT or surgery can be used to eradicate TKI-resistant subpopulations with enhanced PFS and prolonged treatment time with TKI, which may lead to increased overall survival as well. Controlled randomized trials to evaluate these effects are necessary and should be combined with advanced functional imaging and diagnostics like biomarker and liquid biopsy studies to further analyze the biological background of resistance development and disease progression.

4.3. Clinical studies Currently there are four international studies investigating the use of SBRT as a method of aggressive local control whilst on TKI therapy. The main limitation of these studies is that none is randomized and that the lack of a comparator group will limit interpretation (Table 1). The single-arm, multi-center phase II trial (NCT02019576) recruiting in Canada aims to evaluate local control at one year in metastases treated with SBRT in 64 patients who present with oligo-progression while receiving first-line TKI treatment (Sunitinib). Whilst this question will add weight to the proof of principle in relation to local ablation for OPD on TKI, this trial is being conducted in patients with renal tumours limiting comparison of the results. A second single-arm phase II trial (NCT01941654) recruiting in China is assessing the addition of SBRT earlier in the course of mutation-positive NSCLC, with the aim of evaluating PFS rate at 1 year following pre-emptive SBRT to residual metabolically active sites of metastatic disease in 34 patients who have an initial response to first-line TKI therapy. This is investigating using SBRT at an earlier timepoint rather than at the point of oligo-progression. Another single-arm phase II trial (NCT01573702) being conducted in the USA is assessing the addition of SBRT for OPD in EGFR mutation positive patients and aims to evaluate PFS with the addition of SBRT to Erlotinib in 40 patients with progression at ≤5 sites of disease (intra and extra-cranial). This includes intracranial disease, which may oligo-progress for reasons of sub-optimal blood brain barrier drug penetration rather than due to development of drug resistant sub-clones. For this reason local radical treatment with either SBRT or surgical resection is considered as standard of care for limited sites of intra-cranial progression.

Conflict of interests None. References [1] B.W. Stewart, C. Wild, International Agency for Research on Cancer, World Health Organization, World cancer report 2014, Ed. Lyon, France Geneva, Switzerland: International Agency for Research on Cancer WHO Press, (2014). [2] L.A. Torre, F. Bray, R.L. Siegel, J. Ferlay, J. Lortet-Tieulent, A. Jemal, Global cancer statistics, 2012, CA. Cancer J. Clin. 65 (2015) 87–108. [3] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2015, CA Cancer J. Clin. 65 (2015) 5–29. [4] C. Lovly, L. Horn, W. Pao, Molecular Profiling of Lung Cancer. My Cancer Genome, 2016, Updated March 28 www.mycancergenome.org/content/disease/lung-cancer/. [5] J.K. Lee, S. Hahn, D.W. Kim, K.J. Suh, B. Keam, T.M. Kim, S.H. Lee, D.S. Heo, Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis, JAMA 311 (2014) 1430–1437. [6] T.S. Mok, Y.L. Wu, S. Thongprasert, C.H. Yang, D.T. Chu, N. Saijo, P. Sunpaweravong, B. Han, B. Margono, Y. Ichinose, Y. Nishiwaki, Y. Ohe, J.J. Yang, B. Chewaskulyong, H. Jiang, E.L. Duffield, C.L. Watkins, A.A. Armour, M. Fukuoka, Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, N. Engl. J. Med. 361 (2009) 947–957. [7] R. Rosell, E. Carcereny, R. Gervais, A. Vergnenegre, B. Massuti, E. Felip, R. Palmero, R. Garcia-Gomez, C. Pallares, J.M. Sanchez, R. Porta, M. Cobo, P. Garrido, F. Longo, T. Moran, A. Insa, F. De Marinis, R. Corre, I. Bover, A. Illiano, E. Dansin, J. de Castro, M. Milella, N. Reguart, G. Altavilla, U. Jimenez, M. Provencio, M.A. Moreno, J. Terrasa, J. Munoz-Langa, J. Valdivia, D. Isla, M. Domine, O. Molinier, J. Mazieres, N. Baize, R. Garcia-Campelo, G. Robinet, D. Rodriguez-Abreu, G. Lopez-Vivanco, V. Gebbia, L. Ferrera-Delgado, P. Bombaron, R. Bernabe, A. Bearz, A. Artal, E. Cortesi, C. Rolfo, M. Sanchez-Ronco, A. Drozdowskyj, C. Queralt, I. de Aguirre, J.L. Ramirez, J.J. Sanchez, M.A. Molina, M. Taron, L. Paz-Ares, Spanish Lung Cancer Group in collaboration with Groupe Francais de P-C, Associazione Italiana Oncologia T. Erlotinib versus standard chemotherapy as first-line treatment for European

56

[8]

[9]

[10]

[11]

[12] [13]

[14]

[15]

[16]

[17]

[18] [19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

L. Basler et al. / Lung Cancer 106 (2017) 50–57 patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial, Lancet Oncol. 13 (2012) 239–246. L.V. Sequist, J.C. Yang, N. Yamamoto, K. O’Byrne, V. Hirsh, T. Mok, S.L. Geater, S. Orlov, C.M. Tsai, M. Boyer, W.C. Su, J. Bennouna, T. Kato, V. Gorbunova, K.H. Lee, R. Shah, D. Massey, V. Zazulina, M. Shahidi, M. Schuler, Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations, J. Clin. Oncol. 31 (2013) 3327–3334. A.T. Shaw, D.W. Kim, K. Nakagawa, T. Seto, L. Crino, M.J. Ahn, T. De Pas, B. Besse, B.J. Solomon, F. Blackhall, Y.L. Wu, M. Thomas, K.J. O’Byrne, D. Moro-Sibilot, D.R. Camidge, T. Mok, V. Hirsh, G.J. Riely, S. Iyer, V. Tassell, A. Polli, K.D. Wilner, P.A. Janne, Crizotinib versus chemotherapy in advanced ALK-positive lung cancer, N. Engl. J. Med. 368 (2013) 2385–2394. B.J. Solomon, T. Mok, D.W. Kim, Y.L. Wu, K. Nakagawa, T. Mekhail, E. Felip, F. Cappuzzo, J. Paolini, T. Usari, S. Iyer, A. Reisman, K.D. Wilner, J. Tursi, F. Blackhall, P. Investigators, First-line crizotinib versus chemotherapy in ALK-positive lung cancer, N. Engl. J. Med. 371 (2014) 2167–2177. J.A. Engelman, P.A. Janne, Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer, Clin. Cancer Res. 14 (2008) 2895–2899. J.F. Gainor, A.T. Shaw, Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer, J. Clin. Oncol. 31 (2013) 3987–3996. L.V. Sequist, B.A. Waltman, D. Dias-Santagata, S. Digumarthy, A.B. Turke, P. Fidias, K. Bergethon, A.T. Shaw, S. Gettinger, A.K. Cosper, S. Akhavanfard, R.S. Heist, J. Temel, J.G. Christensen, J.C. Wain, T.J. Lynch, K. Vernovsky, E.J. Mark, M. Lanuti, A.J. Iafrate, M. Mino-Kenudson, J.A. Engelman, Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Sci. Transl. Med. 3 (2011) 75ra26. S. Novello, F. Barlesi, R. Califano, T. Cufer, S. Ekman, M.G. Levra, K. Kerr, S. Popat, M. Reck, S. Senan, G.V. Simo, J. Vansteenkiste, S. Peters, E.G. Committee, Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann. Oncol. 27 (2016) v1–v27. S. Kobayashi, T.J. Boggon, T. Dayaram, P.A. Janne, O. Kocher, M. Meyerson, B.E. Johnson, M.J. Eck, D.G. Tenen, B. Halmos, EGFR mutation and resistance of non-small-cell lung cancer to gefitinib, N. Engl. J. Med. 352 (2005) 786–792. W. Pao, V.A. Miller, K.A. Politi, G.J. Riely, R. Somwar, M.F. Zakowski, M.G. Kris, H. Varmus, Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain, PLoS Med. 2 (2005) e73. C.H. Yun, K.E. Mengwasser, A.V. Toms, M.S. Woo, H. Greulich, K.K. Wong, M. Meyerson, M.J. Eck, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP, Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 2070–2075. D.R. Camidge, W. Pao, L.V. Sequist, Acquired resistance to TKIs in solid tumours: learning from lung cancer, Nat. Rev. Clin. Oncol. 11 (2014) 473–481. P.A. Janne, J.C. Yang, D.W. Kim, D. Planchard, Y. Ohe, S.S. Ramalingam, M.J. Ahn, S.W. Kim, W.C. Su, L. Horn, D. Haggstrom, E. Felip, J.H. Kim, P. Frewer, M. Cantarini, K.H. Brown, P.A. Dickinson, S. Ghiorghiu, M. Ranson, AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer, N. Engl. J. Med. 372 (2015) 1689–1699. J. Yang, S.S. Ramalingam, P.A. Janne, M. Cantarini, T. Mitsudomi, LBA2 PR: osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated phase 1 (P1) and pooled phase 2 (P2) results, J. Thorac. Oncol. 11 (2016) S152–153. H.A. Yu, M.E. Arcila, N. Rekhtman, C.S. Sima, M.F. Zakowski, W. Pao, M.G. Kris, V.A. Miller, M. Ladanyi, G.J. Riely, Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers, Clin. Cancer Res. 19 (2013) 2240–2247. J.L. Kuiper, D.A. Heideman, E. Thunnissen, M.A. Paul, A.W. van Wijk, P.E. Postmus, E.F. Smit, Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients, Lung Cancer 85 (2014) 19–24. E.M. Berge, R.C. Doebele, Targeted therapies in non-small cell lung cancer: emerging oncogene targets following the success of epidermal growth factor receptor, Semin. Oncol. 41 (2014) 110–125. D.B. Costa, S. Kobayashi, S.S. Pandya, W.L. Yeo, Z. Shen, W. Tan, K.D. Wilner, CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib, J. Clin. Oncol. 29 (2011) e443–445. T.H. Marsilje, W. Pei, B. Chen, W. Lu, T. Uno, Y. Jin, T. Jiang, S. Kim, N. Li, M. Warmuth, Y. Sarkisova, F. Sun, A. Steffy, A.C. Pferdekamper, A.G. Li, S.B. Joseph, Y. Kim, B. Liu, T. Tuntland, X. Cui, N.S. Gray, R. Steensma, Y. Wan, J. Jiang, G. Chopiuk, J. Li, W.P. Gordon, W. Richmond, K. Johnson, J. Chang, T. Groessl, Y.Q. He, A. Phimister, A. Aycinena, C.C. Lee, B. Bursulaya, D.S. Karanewsky, H.M. Seidel, J.L. Harris, P.Y. Michellys, Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials, J. Med. Chem. 56 (2013) 5675–5690. L. Friboulet, N. Li, R. Katayama, C.C. Lee, J.F. Gainor, A.S. Crystal, P.Y. Michellys, M.M. Awad, N. Yanagitani, S. Kim, A.C. Pferdekamper, J. Li, S. Kasibhatla, F. Sun, X. Sun, S. Hua, P. McNamara, S. Mahmood, E.L. Lockerman, N. Fujita, M. Nishio, J.L. Harris, A.T. Shaw, J.A. Engelman, The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer, Cancer Discov. 4 (2014) 662–673. A.T. Shaw, J.A. Engelman, Ceritinib in ALK-rearranged non-small-cell lung cancer, N. Engl. J. Med. 370 (2014) 2537–2539.

[28] D.W. Kim, R. Mehra, D.S. Tan, E. Felip, L.Q. Chow, D.R. Camidge, J. Vansteenkiste, S. Sharma, T. De Pas, G.J. Riely, B.J. Solomon, J. Wolf, M. Thomas, M. Schuler, G. Liu, A. Santoro, S. Sutradhar, S. Li, T. Szczudlo, A. Yovine, A.T. Shaw, Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial, Lancet Oncol. 17 (2016) 452–463. [29] H-L. Roche, ALEX Study: A Randomized, Phase III Study Comparing Alectinib With Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer Participants, https://clinicaltrials.gov. [30] R. Katayama, C.M. Lovly, A.T. Shaw, Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine, Clin. Cancer Res. 21 (2015) 2227–2235. [31] S. Hellman, R.R. Weichselbaum, Oligometastases, J. Clin. Oncol. 13 (1995) 8–10. [32] Y. Fong, L.H. Blumgart, A.M. Cohen, Surgical treatment of colorectal metastases to the liver, CA Cancer J. Clin. 45 (1995) 50–62. [33] T.A. Aloia, J.N. Vauthey, E.M. Loyer, D. Ribero, T.M. Pawlik, S.H. Wei, S.A. Curley, D. Zorzi, E.K. Abdalla, Solitary colorectal liver metastasis: resection determines outcome, Arch. Surg. 141 (2006) 460–466, discussion 466–467. [34] U. Pastorino, M. Buyse, G. Friedel, R.J. Ginsberg, P. Girard, P. Goldstraw, M. Johnston, P. McCormack, H. Pass, J.B. Putnam Jr., International Registry of Lung M. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases, J. Thorac. Cardiovasc. Surg. 113 (1997) 37–49. [35] M.R. Folkert, R. Timmerman, Review of treatment options for oligometastatic non-small cell lung cancer, Clin. Adv. Hematol. Oncol. 13 (2015) 186–193. [36] T. Inoue, N. Katoh, H. Aoyama, R. Onimaru, H. Taguchi, S. Onodera, S. Yamaguchi, H. Shirato, Clinical outcomes of stereotactic brain and/or body radiotherapy for patients with oligometastatic lesions, Jpn. J. Clin. Oncol. 40 (2010) 788–794. [37] C. Collen, N. Christian, D. Schallier, M. Meysman, M. Duchateau, G. Storme, M. De Ridder, Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients, Ann. Oncol. 25 (2014) 1954–1959. [38] D. Owen, K.R. Olivier, C.S. Mayo, R.C. Miller, K. Nelson, H. Bauer, P.D. Brown, S.S. Park, D.J. Ma, Y.I. Garces, Outcomes of stereotactic body radiotherapy (SBRT) treatment of multiple synchronous and recurrent lung nodules, Radiat. Oncol. 10 (2015) 43. [39] K.E. Rusthoven, S.F. Hammerman, B.D. Kavanagh, M.J. Birtwhistle, M. Stares, D.R. Camidge, Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis, Acta Oncol. 48 (2009) 578–583. [40] R.C. Doebele, X. Lu, C. Sumey, D.A. Maxson, A.J. Weickhardt, A.B. Oton, P.A. Bunn Jr., A.E. Baron, W.A. Franklin, D.L. Aisner, M. Varella-Garcia, D.R. Camidge, Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer, Cancer 118 (2012) 4502–4511. [41] A. Ashworth, G. Rodrigues, G. Boldt, D. Palma, Is there an oligometastatic state in non-small cell lung cancer: a systematic review of the literature, Lung Cancer 82 (2013) 197–203. [42] H.A. Yu, C.S. Sima, J. Huang, S.B. Solomon, A. Rimner, P. Paik, M.C. Pietanza, C.G. Azzoli, N.A. Rizvi, L.M. Krug, V.A. Miller, M.G. Kris, G.J. Riely, Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors, J. Thorac. Oncol. 8 (2013) 346–351. [43] R.C. Doebele, A.B. Pilling, D.L. Aisner, T.G. Kutateladze, A.T. Le, A.J. Weickhardt, K.L. Kondo, D.J. Linderman, L.E. Heasley, W.A. Franklin, M. Varella-Garcia, D.R. Camidge, Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer, Clin. Cancer Res. 18 (2012) 1472–1482. [44] T. Yoshida, K. Yoh, S. Niho, S. Umemura, S. Matsumoto, H. Ohmatsu, Y. Ohe, K. Goto, RECIST progression patterns during EGFR tyrosine kinase inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation, Lung Cancer 90 (2015) 477–483. [45] H. Al-Halabi, K. Sayegh, S.R. Digamurthy, A. Niemierko, Z. Piotrowska, H. Willers, L.V. Sequist, Pattern of failure analysis in metastatic EGFR-Mutant lung cancer treated with tyrosine kinase inhibitors to identify candidates for consolidation stereotactic body radiation therapy, J. Thorac. Oncol. 10 (2015) 1601–1607. [46] K. Aitken, S. Popat, C. Nutting, F. McDonald, 76: Patterns of extra-cranial disease progression in epidermal growth factor receptor (EGFR) mutant metastatic non-small cell lung cancer (NSCLC) patients on a tyrosine kinase inhibitor (TKI), Lung Cancer 87 (2017) S30. [47] J.E. Chaft, G.R. Oxnard, C.S. Sima, M.G. Kris, V.A. Miller, G.J. Riely, Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design, Clin. Cancer Res. 17 (2011) 6298–6303. [48] J. Chmielecki, J. Foo, G.R. Oxnard, K. Hutchinson, K. Ohashi, R. Somwar, L. Wang, K.R. Amato, M. Arcila, M.L. Sos, N.D. Socci, A. Viale, E. de Stanchina, M.S. Ginsberg, R.K. Thomas, M.G. Kris, A. Inoue, M. Ladanyi, V.A. Miller, F. Michor, W. Pao, Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling, Sci. Transl. Med. 3 (2011) 90ra59. [49] K. Ito, O. Hataji, H. Kobayashi, A. Fujiwara, M. Yoshida, C.N. D’Alessandro-Gabazza, H. Itani, M. Tanigawa, T. Ikeda, K. Fujiwara, H. Fujimoto, T. Kobayashi, E.C. Gabazza, O. Taguchi, N. Yamamoto, Sequential therapy with crizotinib and alectinib in ALK-rearranged non-small cell lung cancer-a multicenter retrospective study, J. Thorac. Oncol. (2016). [50] S. Watanabe, H. Hayashi, K. Okamoto, K. Fujiwara, Y. Hasegawa, H. Kaneda, K. Tanaka, M. Takeda, K. Nakagawa, Progression-free and overall survival of

L. Basler et al. / Lung Cancer 106 (2017) 50–57

[51]

[52]

[53]

[54]

[55]

[56]

[57] [58]

[59]

patients with ALK rearrangement-positive non-small cell lung cancer treated sequentially with crizotinib and alectinib, Clin. Lung Cancer (2016). K. Park, C.J. Yu, S.W. Kim, M.C. Lin, V. Sriuranpong, C.M. Tsai, J.S. Lee, J.H. Kang, K.C. Chan, P. Perez-Moreno, P. Button, M.J. Ahn, T. Mok, First-line erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in asian patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer: the ASPIRATION study, JAMA Oncol. 2 (2016) 305–312. J.C. Soria, Y.L. Wu, K. Nakagawa, S.W. Kim, J.J. Yang, M.J. Ahn, J. Wang, J.C. Yang, Y. Lu, S. Atagi, S. Ponce, D.H. Lee, Y. Liu, K. Yoh, J.Y. Zhou, X. Shi, A. Webster, H. Jiang, T.S. Mok, Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial, Lancet Oncol. 16 (2015) 990–998. B. Halmos, N.A. Pennell, P. Fu, S. Saad, S. Gadgeel, G.A. Otterson, T. Mekhail, M. Snell, J.P. Kuebler, N. Sharma, A. Dowlati, Randomized phase II trial of erlotinib beyond progression in advanced erlotinib-responsive non-small cell lung cancer, Oncologist 20 (2015) 1298–1303. P.W. Sperduto, N. Kased, D. Roberge, Z. Xu, R. Shanley, X. Luo, P.K. Sneed, S.T. Chao, R.J. Weil, J. Suh, A. Bhatt, A.W. Jensen, P.D. Brown, H.A. Shih, J. Kirkpatrick, L.E. Gaspar, J.B. Fiveash, V. Chiang, J.P. Knisely, C.M. Sperduto, N. Lin, M. Mehta, Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases, J. Clin. Oncol. 30 (2012) 419–425. P.W. Sperduto, S.T. Chao, P.K. Sneed, X. Luo, J. Suh, D. Roberge, A. Bhatt, A.W. Jensen, P.D. Brown, H. Shih, J. Kirkpatrick, A. Schwer, L.E. Gaspar, J.B. Fiveash, V. Chiang, J. Knisely, C.M. Sperduto, M. Mehta, Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients, Int. J. Radiat. Oncol. Biol. Phys. 77 (2010) 655–661. A.C. Tree, V.S. Khoo, R.A. Eeles, M. Ahmed, D.P. Dearnaley, M.A. Hawkins, R.A. Huddart, C.M. Nutting, P.J. Ostler, N.J. van As, Stereotactic body radiotherapy for oligometastases, Lancet Oncol. 14 (2013) e28–37. C.T. Bradley, V.E. Strong, Surgical management of adrenal metastases, J. Surg. Oncol. 109 (2014) 31–35. S.N. Kalkanis, D. Kondziolka, L.E. Gaspar, S.H. Burri, A.L. Asher, C.S. Cobbs, M. Ammirati, P.D. Robinson, D.W. Andrews, J.S. Loeffler, M. McDermott, M.P. Mehta, T. Mikkelsen, J.J. Olson, N.A. Paleologos, R.A. Patchell, T.C. Ryken, M.E. Linskey, The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline, J. Neurooncol. 96 (2010) 33–43. G.N. Gan, A.J. Weickhardt, B. Scheier, R.C. Doebele, L.E. Gaspar, B.D. Kavanagh, D.R. Camidge, Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib, Int. J. Radiat. Oncol. Biol. Phys. 88 (2014) 892–898.

57

[60] C. Park, L. Papiez, S. Zhang, M. Story, R.D. Timmerman, Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy, Int. J. Radiat. Oncol. Biol. Phys. 70 (2008) 847–852. [61] P. Iyengar, B.D. Kavanagh, Z. Wardak, I. Smith, C. Ahn, D.E. Gerber, J. Dowell, R. Hughes, R. Abdulrahman, D.R. Camidge, L.E. Gaspar, R.C. Doebele, P.A. Bunn, H. Choy, R. Timmerman, Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer, J. Clin. Oncol. 32 (2014) 3824–3830. [62] H.J. Kim, W.S. Kim, H. Kwon do, Y.H. Cho, C.M. Choi, Effects of an epithelial growth factor receptor-tyrosine kinase inhibitor add-on in stereotactic radiosurgery for brain metastases originating from non-small-cell lung cancer, J. Korean Neurosurg. Soc. 58 (2015) 205–210. [63] A.L. Schwer, D.M. Damek, B.D. Kavanagh, L.E. Gaspar, K. Lillehei, K. Stuhr, C. Chen, A phase I dose-escalation study of fractionated stereotactic radiosurgery in combination with gefitinib in patients with recurrent malignant gliomas, Int. J. Radiat. Oncol. Biol. Phys. 70 (2008) 993–1001. [64] Y. Wang, E. Wang, L. Pan, J. Dai, N. Zhang, X. Wang, X. Liu, G. Mei, X. Sheng, A new strategy of CyberKnife treatment system based radiosurgery followed by early use of adjuvant bevacizumab treatment for brain metastasis with extensive cerebral edema, J. Neurooncol. 119 (2014) 369–376. [65] Z. Wang, X.X. Zhu, X.H. Wu, B. Li, T.Z. Shen, Q.T. Kong, J. Li, Z.B. Liu, W.R. Jiang, Y. Wang, B. Hou, Gefitinib combined with stereotactic radiosurgery in previously treated patients with advanced non-small cell lung cancer, Am. J. Clin. Oncol. 37 (2014) 148–153. [66] S.D. Brown, R.L. Warren, E.A. Gibb, S.D. Martin, J.J. Spinelli, B.H. Nelson, R.A. Holt, Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival, Genome Res. 24 (2014) 743–750. [67] S.J. Dovedi, A.L. Adlard, G. Lipowska-Bhalla, C. McKenna, S. Jones, E.J. Cheadle, I.J. Stratford, E. Poon, M. Morrow, R. Stewart, H. Jones, R.W. Wilkinson, J. Honeychurch, T.M. Illidge, Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade, Cancer Res. 74 (2014) 5458–5468. [68] E.B. Golden, A. Chhabra, A. Chachoua, S. Adams, M. Donach, M. Fenton-Kerimian, K. Friedman, F. Ponzo, J.S. Babb, J. Goldberg, S. Demaria, S.C. Formenti, Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial, Lancet Oncol. 16 (2015) 795–803. [69] C. Twyman-Saint Victor, A.J. Rech, A. Maity, R. Rengan, K.E. Pauken, E. Stelekati, J.L. Benci, B. Xu, H. Dada, P.M. Odorizzi, R.S. Herati, K.D. Mansfield, D. Patsch, R.K. Amaravadi, L.M. Schuchter, H. Ishwaran, R. Mick, D.A. Pryma, X. Xu, M.D. Feldman, T.C. Gangadhar, S.M. Hahn, E.J. Wherry, R.H. Vonderheide, A.J. Minn, Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer, Nature 520 (2015) 373–377.