Improved OS Observed When Aggressive Radiation, Surgery Is Added to NSCLC Therapy

Daniel Gomez, MD

Adding aggressive, local radiation or surgery to frontline systemic therapy in patients with stage IV non—small cell lung cancer (NSCLC) whose disease has spread to a limited number of sites resulted in improved overall survival (OS), according to findings presented by Daniel Gomez, MD, and colleagues at the 60th Annual Meeting of the American Society for Radiation Oncology in San Antonio, Texas.¹

After undergoing frontline systemic therapy, consisting of either 4 or more cycles of standard chemotherapy (platinum doublet therapy) or 3 or more months of drugs that target tumor blood vessel growth (EGFR or ALK inhibitors for EGFR mutations/ ALK rearrangements), patients with 3 or fewer nonprogressing lesions were randomized to receive either surgery and/or radiation at the tumor site (n = 25), known as local consolidative therapy (LCT), or systemic maintenance therapy and observation (MT/O; n = 24). Other eligibility criteria included an ECOG performance status of 0 to 2. The primary endpoint of the trial was progression-free survival (PFS), powered for 4 months on MT/O versus 7 months on LCT. Secondary endpoints were OS, safety, toxicity, and time to appearance of new lesions. Importantly, patients were allowed to crossover at the time of disease progression. 

“In lieu of stratification, the trial was conducted with the incorporation of balanced randomization based on 5 disease factors,” said Gomez, of The University of Texas MD Anderson Cancer Center. “These factors included number of metastases, response to first-line systemic therapy, N0/N1 versus N2/N3, CNS [central nervous system] versus no CNS metastases, and EGFR/ALK alteration versus wild type.”

Gomez noted that LCT benefit in PFS had been demonstrated in at least 4 prospective randomized trials in patients with lung,^2,3prostate,⁴and colorectal cancers.⁵Determining whether PFS benefit translates to OS improvement was particularly important in this study because of the opportunity for patients to crossover between arms. In addition, the investigators wanted to determine whether applying “late LCT” (ie, at the time of disease progression) leads to a similar benefit in OS when LCT is given early in the treatment regimen.

The investigators determined in the extended follow-up of 38.8 months that median PFS was 4.4 months in the MT/O arm (95% CI, 2.2-8.3) versus 14.4 months in the LCT arm (95% CI, 7.4-23.1;P= .022). The median OS result was even more dramatic, with patients in the MT/O arm demonstrating 17.0 months versus 41.2 months in the LCT arm (HR, 0.40; 95% CI, 10.1-39.8;P= .017). Gomez reported that in both arms, patients who received complete LCT at the time of progression did better than those who did not receive complete LCT (P= .034). Additionally, neither treatment arm saw any additional grade 3 or higher toxicities than previously reported.

“We found that adding radiation or surgery to target all sites of disease increases the time it takes for the cancer to return or spread, and it also improves overall survival time. But the overall survival results were more impressive than anticipated,” said Gomez.

Gomez and colleagues noted that for patients with oligometastatic disease that does not progress after frontline therapy, LCT improves PFS and is associated with an improvement in OS compared with MT/O. Additionally, survival after progression improved in the LCT arm. The investigators noted that patient subgroups with less nodal burden, fewer metastases, and no CNS metastases appeared to benefit more from LCT.

Gomez suggested that next steps in research should focus on expanding trials in oligometastatic NSCLC that contain large numbers of patients that use OS as an endpoint—because results from this study suggest strong evidence for LCT—assess PFS/OS endpoint in specific subpopulations, and increase the use of correlative analyses to determine predictive/prognostic biomarkers that can better select patients in a true oligometastatic state.

“The patients initially treated with MT/O had the option to receive surgery or radiation if their cancer spread during the trial. Exploratory analyses suggest that aggressively treating all disease sites at the time of progression improved outcomes for these patients compared [with] patients who did not receive late local therapy. Thus, there may be a benefit to either early or late radiation/surgery in the setting of limited metastatic disease,” concluded Gomez.

References:

1. Gomez DR, Tang C, Zhang J, et al. Local consolidative therapy (LCT) improves overall survival (OS) compared to maintenance therapy/observation in oligometastatic non-small cell lung cancer (NSCLC): final results of a multicenter, randomized, controlled phase 2 trial. In: Presented at: 60th Annual Meeting of the American Society for Radiation Oncology; October 21-24, 2018; San Antonio, TX. Abstract LBA-3.
2. Gomez DR, Blumenschein GR Jr, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17(12):1672-1682. doi: 10.1016/S1470- 2045(16)30532-0.
3. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2018;4(1):e173501. doi: 10.1001/jamaoncol.2017.3501.
4. Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018;36(5):446-453. doi: 10.1200/JCO.2017.75.4853.
5. Ruers T, Van Coevorden F, Punt CJ, et al; European Organisation for Research and Treatment of Cancer (EORTC), Gastro-Intestinal Tract Cancer Group, Arbeitsgruppe Lebermetastasen und tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO), National Cancer Research Institute Colorectal Clinical Study Group (NCRI CCSG). Local treatment of unresectable colorectal liver metastases: results of a randomized phase II trial. J Natl Cancer Inst. 2017;109(9). doi: 10.1093/jnci/djx015.