Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene addicted non-small cell lung cancer

Abstract

Introduction

Many patients with oncogene driven non-small cell lung cancer treated with TKIs experience limited sites of disease progression. This study investigated retrospectively the benefits of local ablative therapy (LAT) to 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.

Materials and 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 non-leptomeningeal CNS and/or ≤4 sites of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same TKI. The subsequent median progression free survival from the time of first progression (PFS2) and pattern of progression were recorded.

Results

PFS1 in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. 25 of 51 (49%) patients who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, 1 with surgery, and continuation of the same targeted therapy. Post LAT, 19/25 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 >6 months of additional disease control.

Introduction

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 due to either inadequate central nervous system (CNS) penetration of the drug in some cases of CNS progression, or to 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 occur 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 prior to widespread dissemination of the resistant clone, disease control may be prolonged until either a new event occurs or resistant clones which have disseminated expand enough to become detectable. Secondly, we hypothesized that there is ongoing benefit from the targeted therapy in other sites of (non-progressing) disease due to 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 re-challenge 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 to those in whom the TKI was permanently discontinued.²⁵ Analogous benefits of 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 have 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

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 (CMOCO) database for ALK+ patients determined by break-apart fluorescent in-situ hybridization (FISH) assay or EGFR mutation positive patients (exon 19 deletions or exon 21 L858R mutations) determined either through direct sequencing or allele specific PCR assays (SNaPshot). 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 CMOCO 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 prior to initiation with erlotinib or crizotinib, date of diagnosis of any known CNS involvement, treatment of any known CNS involvement prior to 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 prior to 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 < 1 year prior to start of therapy), former (quit ≥ 1 year prior to start of therapy), or never (<100 lifetime cigarettes).

All ALK+ patients received crizotinib (Xalkori, Pfizer, La Jolla, CA) starting at 250mg PO BiD on either the phase I expansion cohort of PROFILE 1001³⁸ or the non-randomized phase II PROFILE 1005 clinical trial,³⁹ and received staging every 8 weeks (PROFILE 1001), or every 6 weeks (PROFILE 1005) with CT or 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 150mg PO daily, with 2 of 27 receiving erlotinib in combination with the IGF-1R monoclonal antibody cixutumumab (Imclone, New York, NY) as part of a clinical trial.^{40, 41}

Baseline and ongoing CNS and body imaging with MRI, CT and/or PET/CT for the 25 of 27 EGFR-MT patients treated off study was performed according to investigator discretion. The 2 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 prior to progression to continue erlotinib alone, and had staging performed from this time according to investigator discretion. 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 (RECIST 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.

Based on institutional practice, patients who progressed on their oral targeted therapy who had either leptomeningeal disease, more than 4 sites of eCNS progression, poor performance status (ECOG ≥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 non-leptomeningeal CNS progression and/or ≤4 sites of eCNS progression, adequate performance status (ECOG ≤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. For those patients who received surgical LAT, the patient was 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 following any SBRT or XRT. PFS2 was measured from the time of first progression until second progression on the same targeted therapy using RECIST 1.1 or death from any cause. Data analysis was performed up to January 1^st 2012.

Statistical analysis

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).

Results

38 ALK+ patients received crizotinib, 28 (74%) of whom had progressed at the time of analysis. 27 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 (63/65, 97%) had adenocarcinoma histology and the median age was 58 years. Collectively, 19/65 (29%) of patients had known CNS metastases prior to commencement with targeted therapy, but 29/65 (45%) patients with no history of CNS metastases did not have MRI or CT imaging of their brain performed in the 3 months prior to commencement on either drug. The median duration of follow up was 20 months. The median progression free survival (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).

Table 1.

Demographics of patients

		ALL PTS	ALK+	EGFR-MT	ALL PTS TBP	ALK + TBP	EGFR-MT TBP
Number		65	38	27	25/51 (49%)	15/28 (54%)	10/23 (43%)
Age (median, yrs)		58	55	60	58	50	59
Range		23 – 80	23 – 80	46 – 75	23 – 75	23 – 72	54 – 75
Female sex		37 (57%)	18 (47%)	19 (70%)	16 (64%)	8 (53%)	8 (80%)
Never smokers		43 (66%)	26 (68%)	17 (63%)	15 (60%)	11 (73%)	4 (40%)
Previous lines Rx
Mean		2.5	3	1.85	2.5	2.9	2.0
Range		0 – 6	1 – 6	1 – 4	0 – 4	1 – 4	0 – 2
CNS status preC1
None		17 (26%)	10 (26%)	7 (26%)	5 (20%)	4 (27%)	1 (10%)
Present		19 (29%)	14 (37%)	5 (18%)	8 (32%)	5 (33%)	3 (30%)
Unknown		29 (45%)	14 (37%)	15 (56%)	12 (48%)	6 (40%)	6 (60%)
PFS1 (months)
Median		10.3	9.0	13.8	9.8	9.0	12.0
95% CI		8.9–13.8	6.5–12.8	8.9–16.4	8.8–13.8	6.5–12.0	6.5–19.0
No events		51	28	23	25	15	10

PTS: patients. ALK +: ALK positive as defined by FISH. TBP: treated beyond progression with local ablative therapy. CNS = central nervous system,

Among 28 ALK+ patients who had progressed at the time of the analysis, 13 (46%) first progressed in the CNS at PFS1 (2 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, 4 with no CNS metastases) prior to commencing crizotinib (7/18, 39%). Among EGFR-MT patients, 5/23 patients (22%) first progressed in the CNS at PFS1 (2 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 (5 with CNS metastases, 5 with no CNS metastases) prior to commencing erlotinib (2/10, 20%).

Of the 28 ALK+ patients who had progressed, 15/28 (54%) received LAT after first progression and were treated beyond progression with crizotinib. Of the 23 EGFR-MT patients who had progressed, 10/23 (43.5%) received LAT after first progression and were treated beyond progression with erlotinib. Overall 25/51 (49%) patients received LAT at first progression. All patients who received LAT recommenced their TKI following 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 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 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 utilizing CT scanning. Thirteen patients (9 ALK+, 4 EGFR-MT) first progressed in the CNS, with 10/13 (77%) patients only having progression in their CNS while still having control of systemic disease outside the CNS. All 6 patients with fewer than 4 CNS metastases were treated with stereotactic radiosurgery (SRS). A single patient with 8 sites of cerebral metastases was treated with SRS to each site at an outside institution. Otherwise all other patients with ≥4 CNS metastases received whole brain radiotherapy (WBRT). The majority of the 15 patients who progressed outside the CNS and were treated with local therapy were treated with SBRT (15–54Gy, median 40Gy), with 8/15 (53%) having a single site of progression treated. Up to 4 eCNS sites were treated (median 2), with the most common sites being bone and lung. One patient underwent an adrenalectomy, and 2 patients were treated with standard radiation therapy to bone metastases (either with 20 Gy in 5 fractions or 30 Gy in 10 fractions). The median time to the initiation of local therapy from the time of PFS1 was 3.7 weeks.

Table 2.

Sites of oligoprogression and LAT treatment modality

	No. PTS	SRS	WBRT	SBRT	XRT	Surgery
CNS as site of first progression
Lesions < 4	6	6		-	-	-
Lesions ≥ 4	7	1	6	-	-	-
eCNS as site of first progression
Bone	7	-	-	5	2	-
Lung	7	-	-	7	-	-
Lymph node	2	-	-	2	-	-
Adrenal	2	-	-	1	-	1
Liver	1	-	-	1	-	-

LAT – local ablative therapy, SRS – stereotactic radiosurgery, WBRT – whole brain radiation therapy. SBRT – stereotactic body radiation therapy, XRT – external beam radiotherapy, CNS – central nervous system of disease, eCNS – extraCNS site of disease

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, Figure 1). The median PFS2 in patients with initial CNS only progression was 7.1 months. Median PFS2 in patients with initial eCNS progression, including 3 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, 6/25 (24%) patients 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% CI 0.92–12.99, p=0.067) but this was not statistically significant.

Table 3.

Outcomes from LAT and continuation of targeted therapy

Site of first progression	Number of patients	PFS1 (months) (CI)	PFS2 (months)(CI)	Site of 2nd progression
CNS	10	10.9 7.3 – 18.3	7.1 1.7 – 11.3	2 (20%)	no prog
				3 (30%)	CNS
				5 (50%)	eCNS
eCNS*	15	9.0 6.5 – 13.8	4.0 2.7 –7.4	4 (27%)	no prog
				3 (20%)	CNS
				8 (53%)	eCNS
All patients	25	9.8 8.8 – 13.8	6.2 3.7 – 8.0	6 (24%)	no prog
				7 (28%)	CNS
				12 (48%)	eCNS

^*includes 3 patients who progressed eCNS and CNS at PFS1. CNS = central nervous system as site of disease. eCNS – extraCNS sites of disease

Figure 1.

PFS1 and PFS1+PFS2 survival curves of (A) All 25 patients treated with LAT; (B) 10 patients treated with LAT who first progressed only in the CNS; (C) 15 patients treated with LAT who first progressed in extra-CNS (eCNS) locations, including 3 patients with simultaneous CNS and eCNS progression.

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 following WBRT, but there were no other documented Grade 3/4 adverse events attributable to radiotherapy (Table 4).

Table 4.

Potential treatment-related toxicity within 6 months of completing LAT

	WBRT (n=6)		Other ablative therapy (N=19)
	Grade 1/2	Grade 3/4	Grade 1/2	Grade 3/4
Alopecia	6	0	0	0
Fatigue	1	2	3	0
Memory Impairment	3	0	0	0
Nausea	1	0	1	0
Anorexia	1	0	1	0
Emotional Lability	2	0	0	0
Headaches	1	0	0	0
Chest wall tenderness	0	0	1	0

LAT – local ablative therapy. WBRT – whole brain radiotherapy

Discussion

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 this approach 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, Figure 2). 49% of patients treated with either erlotinib or crizotinib who progressed at our institution were deemed appropriate for this treatment strategy.

Table 5.

Based on the practices within this study, suggested criteria for considering local ablative therapy of oligoprogressive disease and treatment with a TKI beyond progression include:
1. ALK positive or EGFR mutant metastatic NSCLC
2. Relevant TKI (e.g. crizotinib or erlotinib) is well tolerated
3. Oligoprogressive disease on TKI therapy, defined as: CNS progression without leptomeningeal disease amenable to WBRT, SRS or surgical resection Progression in ≤ 4 extra-CNS sites amenable to SBRT, XRT or surgical resection

WBRT – whole brain radiation therapy; SRS- stereotactic radiosurgery; SBRT – stereotactic body radiation therapy; XRT – conventionally fractionated radiation therapy

Figure 2.

Proposed schema for incorporating local ablative therapy (LAT) into therapy at time of first progression with ALK+ or EGFR-MT NSCLC patients treated with TKI therapy.

Patients treated with crizotinib or erlotinib in this series had a median PFS1 of 10.3 months, consistent with literature precedent.^1–6 While retrospective series of radiotherapy used in oligometastatic disease at diagnosis in metastatic NSCLC report good local control rates and better overall survival than 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 ≤ 4 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 following LAT of isolated CNS progression in 17 NSCLC patients who had achieved at least stable disease >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 following 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 we felt was unlikely to be suited to a local treatment approach.⁵⁰ Strikingly, nearly half (13/28, 46%) of all ALK+ patients progressed first in the CNS, with the majority (11/13) 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 pre-existed. 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 due to 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 exists.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 towards 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 to 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% CI 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 while 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. Based on institutional precedent, we limited the number of eCNS lesions considered for LAT to ≤4 sites, and in most cases the number of CNS lesions considered for SRS as opposed to WBRT to <4. 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 while 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 vs 12.8 months), we do not appear to have preselected a more indolent population for LAT within this study. While 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 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 4/25 of the LAT group and 10/26 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, Figure 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 utilizing standardized restaging technology (PET/MRI) at defined intervals to minimize bias.