FOR A SUBSET of patients with stage IV lung cancer, aggressive treatment may improve overall survival, according to data presented at the 2018 Annual Meeting of the American Society for Radiation Oncology (ASTRO).¹

The results of the phase II study showed that with long-term follow-up, local consolidative therapy in patients with oligometastatic non–small cell lung cancer (NSCLC) who did not experience disease progression after front-line systemic therapy was associated with improved overall and progression-free survival vs maintenance therapy or observation. Local consolidative therapy was also associated with acceptable tolerance, the authors of the study noted.

Daniel R. Gomez, MD

“To our knowledge, this study, in conjunction with data from the COMET study (presented at the same meeting), represents the first randomized data showing an overall benefit for local ablative therapy in patients with oligometastatic NSCLC that does not progress after front-line systemic therapy,” said Daniel R. Gomez, MD, Associate Medical Director and Service Chief of Thoracic Section in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center, Houston. “Complete local consolidative therapy at the time of disease progression may also improve overall survival.”

As Dr. Gomez explained, the concept of oligometastasis gained recognition more than 2 decades ago with the pioneering work of Drs. Ralph Weichselbaum and Samuel Hellman, who attempted to define a subset of patients in between a locally advanced state and true metastases who could still potentially be “cured” with aggressive measures. Although a number of single-arm studies have been conducted in the intervening years, said Dr. Gomez, there previously was a paucity of randomized data comparing standard systemic therapy, which has been the paradigm for decades, vs more aggressive therapy in conjunction with systemic therapy in this context.

To examine this question, Dr. Gomez, in conjunction with Dr. John Heymach in thoracic medical oncology and Dr. Stephen Swisher in thoracic surgery, initiated this phase II randomized study in 2012 with the University of Colorado and London-Ontario Cancer Center. The primary eligibility criteria included stage IV NSCLC and up to three metastases after standard front-line systemic therapy. According to Dr. Gomez, eligible patients had “induced oligometastatic disease,” having had the number of their metastases reduced to three or fewer with systemic therapy prior to enrollment.

“To our knowledge, this study [and the COMET study] represents the first randomized data showing an overall benefit for local ablative therapy in oligometastatic NSCLC that does not progress after front-line systemic therapy.”

— Daniel R. Gomez, MD

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Front-line therapy consisted of 4 or more cycles of platinum doublet therapy or 3 or more months of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitors for patients with EGFR mutations and ALK rearrangements, respectively. Investigators then randomly assigned patients to receive either standard maintenance therapy or observation vs local consolidative therapy, defined as radiation or surgery to all remaining active sites of disease followed by choice of systemic therapy. The study’s primary endpoint was progression-free survival, with secondary endpoints including overall survival, toxicity, and time to appearance of a new lesion.

2-Year Increase in Survival Rates

AS DR. GOMEZ reported, although the study was powered for 94 patients, the trial was closed prematurely after accrual and randomization of 49 patients. The initial results, which were published in The Lancet Oncology in 2016,² were for a median follow-up of 12.4 months and showed a substantial increase in progression-free survival in the experimental arm vs standard therapy (11.9 months vs 3.9 months). At the 2018 ASTRO Annual Meeting, Dr. Gomez presented new results that included updated data on progression-free and overall survival as well as toxicity for 38.8 months of patient follow-up (range, 28.3–61.4 months).

“Since 2016, the benefit of consolidative therapy with respect to progression-free survival has been demonstrated in a similar cohort of patients in at least four prospective randomized trials,” said Dr. Gomez. “However, the big question is, does a benefit in progression-free survival translate to an improvement in overall survival?”

The extended follow-up data showed that patients who received radiation therapy or surgery to all remaining active sites of disease had progression-free-survival rates of 14.4 months vs 4.4 months for patients receiving standard treatment and observation (P = .022), with no additional high-grade toxicity in either arm. However, the difference in overall survival was even more dramatic. Patients receiving local consolidative therapy had a median overall survival rate of 41.2 months compared with 17.0 months for patients receiving standard maintenance therapy or observation (P = .017).

According to Dr. Gomez, the question of survival benefit is particularly relevant in this trial because crossover was allowed between the arms. Thus, patients with disease progression on standard therapy could then receive aggressive treatment to all metastatic sites. Additional analysis showed that the median survival after disease progression was significantly higher in patients receiving consolidation radiotherapy at the time of disease progression (37.6 months) vs maintenance therapy or observation (9.4 months, P = .034). Moreover, said Dr. Gomez, this result was “arm-agnostic.” Patients who received complete local consolidative therapy at the time of disease progression—in either arm—did better than those who did not.

“This evidence suggests that patients who receive complete local consolidative therapy at the time of disease progression can offset any detriment in overall survival to some extent by receiving aggressive therapy at the time that they experience disease progression,” said Dr. Gomez. However, it was noted that less than 50% of patients in either arm were eligible for complete local consolidative therapy at the time of disease progression.

Finally, a subgroup analysis of prognostic factors showed that N0/ N1 disease, between zero and one metastasis after systemic therapy, and the absence of metastases of the central nervous system seemed to trend toward a benefit with local consolidative therapy after front-line systemic therapy. Nevertheless, Dr. Gomez acknowledged that the small number of patients (n = 49) complicated subgroup analyses.

“A second limitation of this study was that it was conducted prior to the advent of immunotherapy in the setting of lung cancer, which has transformed the paradigm of treatment in many scenarios including stage IV disease.” Thus, this paradigm will need to be tested in larger trials, such as NRG-LU002, and other studies that focus on patients receiving immunotherapy or targeted agents,” Dr. Gomez added. ■

DISCLOSURE: Dr. Gomez has financial relationships with Varian, Merck, AstraZeneca, Bristol-Myers Squibb, Driver Oncology, US Oncology, and RefleXion Medical.

REFERENCES

1. Gomez DR, Tang C, Zhang J, et al: Local consolidative therapy improves overall survival compared to maintenance therapy/observation in oligometastatic non-small cell lung cancer. 2018 ASTRO Annual Meeting. Abstract LBA3. Presented October 21, 2018.

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 17:1672-1682, 2016.