RT FOR OLIGOMETASTATIC NSCLC

Consolidation treatment with stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy almost tripled progression-free survival (PFS) in patients with limited metastatic non–small cell lung cancer (NSCLC) compared to maintenance chemotherapy alone.

A new analysis showed that there was a statistically significant improvement in PFS from 3.5 to 9.7 months with the addition of consolidative radiotherapy to maintenance chemotherapy for patients with limited metastatic NSCLC (hazard ratio [HR], 0.304; 95% confidence interval [CI], 0.113 - 0.815; P = .01).

"There was a near tripling of PFS, and we hope and expect it will correlate with overall survival, but at the time of this analysis, median overall survival not yet been reached," said Puneeth Iyengar, MD, PhD, lead author of the study and an assistant professor of radiation oncology at the University of Texas Southwestern Medical Center in Dallas.

Dr Iyengar presented the findings during the plenary session of the American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting.

The study was also published online in JAMA Oncology to coincide with the meeting.

Dr Iyengar pointed out that previous studies in metastatic solid tumors and primary sites suggest a benefit of adding local therapy in the form of radiation or surgery to systemic therapy options for patients with limited metastatic NSCLC.

"We tried to identify a subset of patients who could potentially benefit from adding local therapy to maintenance systemic therapy for limited metastatic NSCLC," he said

PFS and Local Control Improved

In this phase 2 study, Dr Iyengar and his colleagues evaluated the effect of SAbR on PFS in patients with limited metastatic NSCLC.

The cohort included 29 patients with stage IV NSCLC who had achieved a partial response or stable disease after induction chemotherapy and who had six or fewer sites of limited metastatic disease, including the primary site. The majority of patients (86%) had tumors with nonsquamous histologies.

Patients were randomly allocated to receive either maintenance chemotherapy alone (15 patients) or combination stereotactic body radiotherapy to all sites followed by maintenance chemotherapy (14 patients). Radiation to metastases was offered as a single fraction (to 21 - 27 Gy), three fractions (to 26.5 - 33 Gy) or five fractions (to 30 - 37.5 Gy).

For the primary tumor, radiation was delivered at total dose of 45 Gy when possible or by 15 fractions of hypofractionated radiotherapy if the primary tumor was centrally located or involved mediastinal nodes.

Chemotherapy choice was left to the discretion of the treating medical oncologists and consisted of pemetrexed, docetaxel, erlotinib, or gemcitabine.

The study's primary endpoint was PFS; secondary endpoints included toxicity, local and distant tumor control, and patterns of failure.

Accrual was halted early after an unplanned interim analysis found a significant improvement in PFS in the SAbR plus maintenance chemotherapy arm. In addition, rates of local control and delay in distant metastases favored combination therapy.

Among patients who received consolidative local therapy, there were no recurrences in original sites of gross disease; there were seven failures in the patients who received only maintenance therapy.

At the time of their analysis, 10 of the 15 patients who received maintenance chemotherapy only experienced disease progression (13 sites), vs 4 of 14 (five sites) of those who received radiotherapy.

"There was a shift in patterns of failure," said Dr Iyengar. "The patients who received local therapy had no failures at the sites that were radiated, whereas patients in the other group failed in areas that would have gotten radiation if they had been in that arm.

"So clearly, local therapy controlled the disease and delayed time to progression," he added. "Failure patterns suggest a shift from local to distant sites."

Toxicity was similar in both groups. In the maintenance chemotherapy–only arm, there were two grade 3 toxicities and one grade 4 toxicity, vs four grade 3 and no grade 4/5 toxicities in the group that received radiation.

Needs Confirmation

"This study is encouraging for patients suffering from metastatic lung cancer, as metastatic lung cancer is incurable, and the standard treatment is chemotherapy alone," commented Kenneth Rosenzweig, MD, professor and system chair of the Department of Radiation Oncology at the Mount Sinai Health System in New York City.

"This study shows that treating small tumors with highly focused stereotactic radiation can improve survival with minimal toxicity and a high level of convenience," he said. "Since this study is so small, its results will need to be confirmed in a larger study."

A phase 3 study, utilizing the same trial design, has been activated by NRG Oncology (NRG LU 002) to answer the question as to the effect of local therapy on overall survival. Another NSCLC-specific phase 3 randomized trial, SARON, that has a similar design (chemotherapy with or without local therapy) has opened in the United Kingdom.

Role of Immunotherapy?

"This trial is further evidence that consolidation radiation therapy in patients who have limited metastatic disease ― defined as six sites, including the primary ― can improve progression-free survival," Henning Willers, MD, director of the Thoracic Radiation Oncology Service at Massachusetts General Hospital in Boston, told Medscape Medical News. 

Dr Willers pointed to a similar phase 2 randomized study that was published last year in Lancet Oncology (Lancet Oncol. 2016;17:1672-1682) that also examined the role of local consolidative therapy for patients with oligometastatic NSCLC. The study was larger than the current one, with a cohort of 74 patients. Results showed that PFS in patients who received local consolidative therapy group was 11.9 months vs 3.9 months in the maintenance treatment group (HR, 0.35; log-rank P = .0054). Adverse events were similar between the two groups.

"They found something very similar, and the studies are very consistent with each other," said Dr Willers. "Most importantly, both trials show that this can be done without added toxicity.

"This needs to be tested in a phase 3 trial, and there are implications for clinical practice, because we do see a number of patients with oligometastatic disease that is amenable to local radiation, such as stereotactic body radiation therapy," he said.

The big question, though, is, where does local consolidative therapy fit with immunotherapy?

"We have now entered the immunotherapy world, and these studies are all in patients who are not getting checkpoint inhibitor treatment," Dr Willers explained.

"The FDA has now approved first-line immune checkpoint inhibitor therapy with chemotherapy in stage IV disease, and we can give pembrolizumab if PD-L1 staining of tumor cells is higher than 50%, and we can give it these inhibitors in second line ― but that is not captured by these trials," he pointed out.

"The big question is, if we are going to pursue the paradigm of consolidation radiation in patients who receive immune checkpoint inhibitor therapy with or without chemotherapy, is there room for consolidation radiation therapy, or do we not need it when the patient is already responding to immune checkpoint inhibition?," Dr Willers noted.

Although phase 3 trials are needed, Dr Willers believes that local radiotherapy may still be beneficial in many patients to prevent local tumor regrowth and metastatic reseeding. "The added benefit is that the release of tumor antigens may help the immune checkpoint inhibitor. So that is an important question for the future ― in the world of immune-oncology, what is the role for this?"

Dr Iyengar has disclosed no relevant financial relationships. Several coauthors report relationships with industry, as noted in the abstract. Dr Willers has disclosed no relevant financial relationships. 

American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting. Abstract LBA-3, presented September 25, 2017.