Time to response, local recurrence better with concurrent treatment

Among melanoma and non-small cell lung cancer (NSCLC) patients with brain metastases, delivering immune checkpoint therapy and radiotherapy concurrently was associated with better outcomes than non-concurrent delivery of the dual treatment in a retrospective review of just over 100 cases.

Concurrent treatment led to improved brain metastasis response and decreased local recurrence compared to immune checkpoint therapy (ICT) and radiotherapy delivered non-concurrently, within 90 days of each other.

The dual treatment effect appeared to be better among patients with melanoma than patients with NSCLC. In multivariate Cox regression adjusting for other confounders, concurrent treatment was associated with the greatest improvement in survival times in this subgroup (hazard ratio, 2.16; 95% CI, 1.18-2.63; P=0.006).

Introduced close to a decade ago, T cell targeted immunomodulators that block the immune checkpoints CTLA-4 and PD1 and PDL1 represented game changers — as single agents or combined with chemotherapy — for a host of different cancers.

Writing in the American Cancer Society journal Cancer, Jack M. Qian, MD, of Dana Farber/Brigham and Women’s Cancer Center, Boston, and colleagues noted that while cancer patients with metastases to the brain have largely been excluded from ICT clinical trials, there is emerging evidence that ICT adds value to radiotherapy in patients with brain metastases secondary to melanoma and NSCLC.

“Early data have suggested that the combination of brain radiotherapy and ICT is reasonably safe and can produce synergistic antitumor activity. However, to our knowledge, there remains a paucity of data regarding the optimal timing of each therapy to maximize synergy,” Qian and colleagues wrote.

Their study was designed to examine the impact of timing of radiotherapy and ICT on outcomes among patients with brain metastases secondary to melanoma and NSCLC.

The study authors identified a total of 199 patients with melanoma or NSCLC and brain metastases consecutively treated with radiotherapy and ICT between 2007 and 2016 at the study institution. Concurrent treatment was defined as radiotherapy delivered on the same day as or in between doses of an ICT course, and all other treatment was considered to be non-concurrent.

Multivariable Cox proportional hazards models were used to assess time to response and local disease recurrence on a per-metastasis basis, using a sandwich estimator to account for intrapatient correlation.

The final cohort included 110 patients with 340 brain metastases, with 102 brain metastases treated concurrently and 238 brain metastases treated non-concurrently.

Response rates were higher with the use of concurrent treatment (70% versus 47%; P<0.001), with correspondingly lower rates of progressive disease (5% versus 26%; P<0.001).

Among the other main findings:

  • On multivariable analysis, concurrent treatment was found to be associated with improved time to response (hazard ratio, 1.76; 95% CI, 1.18-2.63P=0.006) and decreased local recurrence (hazard ratio, 0.42; 95% CI, 0.23-0.78P=0.006).
  • This effect appeared to be greater for the melanoma subgroup (HR, 0.37; 95% CI, 0.19-0.74) compared with the NSCLC subgroup (HR, 0.94; 95% CI, 0.28-3.20).
  • After a median follow-up of 12.6 months, only 1 of 103 metastases showing a complete response later exhibited disease progression.

“Overall, the results of the current study lend support to conducting a prospective trial regarding the addition of concurrent ICT to brain-directed radiotherapy, in which the primary role of ICT actually might be as a radiosensitizer,” Qian and colleagues wrote.

They noted that preclinical research suggests the activity of ICT alone against brain metastases “requires the presence of extracranial antigens and the activation of peripheral immune cells, rather than any direct effect on the intracranial tumor microenvironment.”

“To our knowledge, the question of whether this remains true when adding radiotherapy is unknown, but emerging evidence has indicated that radiotherapy has additional immunomodulatory effects on the tumor microenvironment rather than just causing immunogenic tumor cell death,” they added.

The study authors also noted that ICT might play a radiosensitizing role, “wherein stimulating antitumor immunity in combination with immunomodulation from radiotherapy overcomes traditional radioresistance.”

“Given the results of the current study, future clinical studies could examine the usefulness of concurrent ICT and radiotherapy in patients for whom local response and local control are especially important (e.g., because of metastasis size or location within the brain, a less favorable histology, or metastases that have already recurred locally despite prior radiotherapy)” they wrote.

  1. Among melanoma and non-small cell lung cancer patients with brain metastases, delivering immune checkpoint therapy and radiotherapy concurrently was associated with better outcomes than non-concurrent delivery of the two treatments.

  2. Concurrent treatment led to improved brain metastasis response and decreased local recurrence compared to immune checkpoint therapy and radiotherapy delivered non-concurrently, within 90 days of each other.

Salynn Boyles, Contributing Writer, BreakingMED

The researchers declared no funding source nor competing interests related to this research.

Cat ID: 24

Topic ID: 78,24,791,24,129,192,925,482