Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Gomez, 2016

Type of study: Multicenter phase II RCT

Setting and country: The trial took place at three institutions: (1) The University of Texas MD Anderson Cancer

Center (Houston, TX), (2) London Health Sciences Center (London, ON), and (3) The

University of Colorado (Aurora, CO).

Funding and conflicts of interest:

Funding: MD Anderson Lung Cancer Priority Fund, MD Anderson Cancer Center Moon Shot Initiative, and Cancer Center Support (Core) Grant CA016672 from the National Cancer Institute, National Institutes of Health.

1 author reports personal fees from Loxo, Ariad, Pfizer, Clovis, and AstraZeneca, grants from Threshold, Ignyta, Mirati, , Abbott Molecular, OxOnx, and Loxo, all outside the submitted work.

Inclusion criteria: (1) diagnosis of

pathologically confirmed NSCLC, (2) stage IV disease according to the 7th edition of the American Joint Committee on Cancer staging system, (3) ≤3 metastases, not including the

primary tumor (as defined below), (4) Eastern Cooperative Oncology Group (ECOG) performance status ≤2, (5) ≥18 years of age, and (6) receipt of standard front line systemic

therapy, defined as (a) ≥4 cycles of platinum doublet chemotherapy, (b) erlotinib or another

approved first line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for ≥3 months if the patient was known to harbor an EGFR mutation, or (c) crizotinib for ≥3

months if the patient was known to have an anaplastic lymphoma kinase (ALK)

rearrangement.

Exclusion criteria: Presuming that the patient met the above conditions, no exclusion criteria existed for prior therapy, other than that bevacizumab was not permitted within 2 weeks of

the initiation of the radiation therapy course.

N total at baseline:

Intervention: 25

Control: 24

Important prognostic factors²:

Age ± SD:

I: 64 ± 10

C: 63 ± 10

Sex:

I: 48% M

C: 42% M

Non-Regional Metastases after Initial Systemic Therapy

0-1

I: 65%

C: 62%

2-3

I: 32%

C: 38%

Synchronous

I: 96%

C: 92%

Adenocarcinoma

I: 84%

C: 75%

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

(Chemo)radiation or resection of all lesions +/− maintenance therapy

Patients who were randomized to the LCT arm were treated with the intent to ablate all residual disease (primary tumor, lymph nodes, and metastatic sites as appropriate) with

surgery, radiation therapy, or both. The type of LCT was determined in consultation with multidisciplinary teams. The choice of dose-fractionation regimen was made by the treating

radiation oncologist, with curative intent when possible. Stereotactic ablative body radiation

(SABR), intermediate hypofractionated radiation (e.g., 15 fractions to the mediastinum), and

concurrent chemoradiation were allowed. After LCT, the choice for maintenance therapy or observation (e.g. crossover) was made at the treating physician’s discretion. Patients on the

LCT arm continued to be followed on this arm until progression, regardless of whether they were treated with systemic therapy after LCT.

Describe control (treatment/procedure/test):

Maintenance therapy/ observation only

Observation was defined as close surveillance, with follow-up as noted below but without

any cytotoxic treatment. Because no single “standard” systemic approach has been accepted, and because the choice between maintenance therapy or observation typically depends on tumor histology and mutation status, the treating physicians for both treatment arms were

given several recommended current FDA-approved regimens, including observation. Acceptable options for maintenance therapy included pemetrexed and bevacizumab (for

non-squamous NSCLC), erlotinib, crizotinib (for patients with ALK rearrangement), and

observation. Patients in the maintenance therapy/ observation arm could also crossover and be treated with LCT at the time of progression. However, if crossover to LCT occurred prior to the time of progression, the event time was censored.

Length of follow-up: Median follow-up time for PFS: 18.7 months.

Incomplete outcome data:

Intervention: n=1 for PFS: no follow-up imaging

Control: 0

Outcome measures and effect size (include 95%CI and p-value if available):

Outcome measure 1 - Overall survival

Number of deaths

I: 6

C: 8

The OS data are immature,

as the median survival time has not been reached in either group.

Outcome measure 2 - Progression free survival

Median PFS time

I: 11.93 months (90% CI 5.72 to 20.90)

C: 3.9 months (90% CI 2.30 to 6.64)

HR: 0.35 (90% CI 0.18 to 0.66), favouring intervention

PFS rate

I: 48%

C: 20%

Outcome measure 3 - Response rate

NR

Outcome measure 4 - Quality of life (secondary analysis)

A total of 31 patients completed the MDASI

questionnaires at baseline, 18 on the LCT arm and 13 on the maintenance therapy arm.

However, by the second follow-up visit (at approximately 16 weeks), the number of patients

completing these questionnaires had dropped to 6 on each arm. It was thus concluded that the results were insufficient at later time points to perform a formal analysis of the QOL data.

Outcome measure 5 - Safety (adverse events and toxicity)

Grade 3 or higher adverse events

I: esophagitis (n=2), anemia (n=1), pneumothorax (n=1), and abdominal pain (n=1)

C: fatigue (n=1) and anemia (n=1)

Grade 4–5 toxicity

None

In the no-LCT arm, three patients crossed over because of toxicity (before disease progression), one with grade 2 elevations in creatinine and grade 2 fatigue, one with grade 3 fatigue, and one with grade 3 anemia. One other patient who remained on the no-LCT arm had significant bilateral lower extremity edema related to pemetrexed maintenance therapy, which resolved upon discontinuation of the pemetrexed.

Author’s conclusion

LCT +/− maintenance therapy for patients with ≤3 metastases from NSCLC that

did not progress after initial systemic therapy improved PFS relative to maintenance therapy alone. These findings imply that aggressive local therapy should be further explored in phase III trials as

a standard treatment option in this clinical scenario.

Remarks

The study was terminated early after treatment of 49 patients (25 LCT, 24 control),

when at a median follow-up time for PFS of 18.7 months, the median PFS time in the LCT group was 11.9 months (90% confidence interval (CI) 5.72 ,20.90) versus 3.9 months (90% CI 2.30, 6.64) in the maintenance group (HR=0.35, 90% CI 0.18,0.66, log rank p=0.005). Toxicity was

similar between groups, with no grade 4–5 events.

Of the 17 patients with progressive disease in the no-LCT arm, 11 received local therapy at the time of progression (6 SABR, 3 surgery only, 1 surgery plus radiation, 1 SABR plus chemoradiation). Of the six patients who did not cross over to LCT, three received further systemic therapy, one chose to pursue a vaccine trial and non-cytotoxic therapy, one did not have local therapy because of poor performance status, and one experienced disease

progression after two cycles of maintenance bevacizumab and thus was given palliative

radiation at that time. Although the radiation was tolerated well, the disease continued to progress and the patient died approximately 3 months later.

Iyengar, 2018

Type of study: Phase II RCT

Setting and country: Texas Southwestern Medical Center, USA

Funding and conflicts of interest:

Funding not reported.

Conflicts of interests: None

Inclusion criteria: Patients were eligible if they were 18 years or older, had a Karnofsky Performance Status score of 70 or better, and had

biopsy-proven metastatic NSCLC. Patients must have received 4 to 6 cycles of first-line platinum-based chemotherapy,

achieving stable disease or a partial response on

imaging by RECIST (Response Evaluation Criteria In Solid Tumors).

Those receiving first-line targeted therapy for EGFR positive and/or ALK-positive NSCLC were excluded. Patients were allowed to have up to 6 sites of extracranial disease (including primary) with no more than 3 sites in the liver or lung identified by diagnostic CT, PET-CT, or magnetic resonance imaging prior to enrollment.

Exclusion criteria: Individuals were ineligible if previously irradiated primary disease progressed within 3 months

of that treatment. Patients with untreated and/or uncontrolled

brain metastases or disease involving the gastrointestinal

tract and skin were ineligible.

N total at baseline:

Intervention: 14

Control: 15

Important prognostic factors²:

Age, median (range)

I: 63.5 (51.0-78.0)

C: 70.0 (51.0-79.0)

Sex:

I: 64.3% M

C: 73.3% M

Nonsquamous

I: 92.9%

C: 80%

Sites of disease prior to induction

chemotherapy, median No. (range)

I: 3 (2-6)

C: 2 (2-5)

Previously treated brain metastases

I: 42.9%

C: 33.3%

Groups comparable at baseline? No

Describe intervention (treatment/procedure/test):

Noninvasive stereotactic ablative radiotherapy

(SAbR) prior to maintenance chemotherapy

All primary sites of disease and identified metastases were treated with external beam radiation. Stereotactic ablative radiotherapy

began within 1 to 2 weeks after randomization to the radiation arm.

Accepted single-fraction cumulative SAbR doses included 21 to 27 Gy (with minor acceptable deviation of ≥16 Gy but <21 Gy per fraction (to convert to rad, multiply by 100)). Accepted 3-fraction cumulative SAbR doses included 26.5 to

33.0Gy (with minor acceptable deviation of ≥24.5Gybut <26.5 Gy). Accepted 5-fraction cumulative SAbRdoses included 30.0 to 37.5 Gy (with minor acceptable deviation of ≥28 Gy but <30

Gy). If the treating radiation oncologist believed that the SAbR fractionation schemes for primary disease did not allow normal tissue constraints to be met, an alternative acceptable prescription was 45 Gy in 15 fractions. All permissible treatment schemas had biologically similar tumor doses per the Universal

SurvivalModel (α = 0.33Gy-1;Do = 1.25Gy; Dq = 1.8 Gy).

Choices of first-line and maintenance chemotherapy were determined by the medical oncology team. Maintenance chemotherapy

included erlotinib, pemetrexed, docetaxel, gemcitabine, or bevacizumab. Maintenance chemotherapy was given until disease progression, intolerable toxic effects, or

death and was initiated within 1week after all radiation on the consolidative arm unless otherwise indicated.

Describe control (treatment/procedure/test):

Maintenance chemotherapy

Choices of first-line and maintenance chemotherapy were determined by the medical oncology team. Maintenance chemotherapy

included erlotinib, pemetrexed, docetaxel, gemcitabine, or bevacizumab. Maintenance chemotherapy was given until disease progression, intolerable toxic effects, or

death and was initiated within 1 week of randomization to the

maintenance-only arm

Length of follow-up: Median (range) follow-up was 9.6 (2.4-30.2) months.

Loss-to-follow-up:

None

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Outcome measure 1 - Overall survival

Median OS was not reached for the SAbR-plus-maintenance

chemotherapy arm, though the study was not powered to show a statistical difference in survival.

Outcome measure 2 - Progression free survival

(Unplanned interim analysis)

Median PFS

I: 9.7 months

C: 3.5 months

HR 0.304 (95% CI 0.113 to 0.815), favouring intervention

Outcome measure 3 - Response rate

NR

Outcome measure 4 - Quality of life

NR

Outcome measure 5 - Safety (adverse events and toxicity)

Grade 1

I: 13

C: 17

Grade 2

I: 5

C: 5

Grade 3

I: 4

C: 2

Grade 4

I: 0

C: 1

Grade 5*

I: 3

C: 6

*While there were several grade 5 events none were

attributable to study interventions.

Author’s conclusion

Consolidative SAbR prior to maintenance chemotherapy

appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local

therapy in limited metastatic settings.

Remarks

The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus maintenance

chemotherapy arm of 9.7 months versus 3.5 months in the maintenance

chemotherapy–alone arm

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Gomez, 2016

the randomization was balanced dynamically on five prognostic

covariates related to PFS per the method of Pocock and Simon.(9) The covariates were (a)

number of sites of disease (0–1 versus. 2–3); (b) response to first-line systemic therapy (stable disease versus. partial response (PR); (c) CNS metastases (yes versus. no); (d) intrathoracic nodal

status (N0/N1 versus. N2/N3), and (e) EGFR/ALK mutation (yes versus. no). After a research nurse

enrolled each patient and entered the above variables, randomization was conducted using

the MD Anderson Department of Biostatistics Clinical Trials Conduct (CTC) website.

Likely

Likely

Likely

Likely

Unlikely

Unlikely

Unlikely, 1 patient with no follow-up imaging was excluded for PFS in the intervention group

Iyengar, 2018

Patients were randomized via permuted block to either maintenance chemotherapy alone or

SAbR followed by maintenance chemotherapy.

Unclear

Unclear

Unclear

Unclear

Unlikely

Unlikely

Unlikely