1. Samson, Kurt

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SAN FRANCISCO-Combining immune checkpoint inhibitors with radiotherapy could prove to be a potential treatment for metastatic non-small cell lung cancer (NSCLC), with an acceptable risk of side effects, especially if radiation is delivered after immune checkpoint inhibitors (ICPIs).

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Toxicity may not be an insurmountable barrier to the combined use of ICPIs with thoracic radiotherapy (TRT), according to a study presented at the 2017 Multidisciplinary Thoracic Cancers Symposium (Abstract 10).


Because it is a relatively new approach, there are concerns the regimen could result in prohibitively high risk of toxicity, but in 29 patients, only 10 percent experienced grade 3 or higher treatment-related pneumonitis. Three additional cases of lower grade pneumonitis also occurred, said lead author Kamran A. Ahmed, MD, a resident in radiation oncology at the Moffitt Cancer Center, Tampa, Fla.


"The use of immune checkpoint inhibitors has become increasingly common in the management of advanced lung cancer," he noted. "There is preclinical rationale to combine the use of RT with ICPI to enhance the efficacy of these agents, but little was known about the potential toxicity of the combination."


Earlier work by the researchers found the combination to be safe and effective against melanoma-related brain metastases. Even so, he said additional research is needed to confirm the findings.


"The findings show the potential for the tolerability and efficacy of this combined approach for treating thoracic tumors," said Ahmed. "Treatment with ICPIs and thoracic radiation carried a modest risk for side effects. Our study indicates the risk of TRT/ICPI-related pneumonitis may be highest when TRT is delivered after ICPI therapy, but these findings should be evaluated further within the context of prospective clinical trials, particularly those that examine the risk of lung toxicity. We strongly advocate for ongoing studies in this area."


Methods, Results

Ahmed and his colleagues retrospectively analyzed clinical records of 29 predominantly metastatic NSCLC patients who had been treated with thoracic RT and several different ICPI therapies at the center. The primary outcome was treatment-related toxicity such as pneumonitis and other types of lung damage.


Fourteen patients received an anti-PD-1 ICPI and three were treated with an anti-PD-L1 inhibitor. Seven received combined anti-PD-1/CTLA-4 and five were administered an anti-PD-/CTLA-4 ICPI. The median interval between ICPI and TRT administration was 2.2 months.


Three of the patients received TRT following ICPI treatment targeting the anti-PD-1 protein, whereas none of the patients who received RT before ICPI therapy experienced severe treatment-related toxicity. The median age at the time of enrollment was 64 years, and 55 percent were female. Most patients presented with NSCLC (79%) and ECOG 1 performance status (69%). The number of metastatic sites ranged from two to eight, with a median of three sites.


Each patient had received RT within the 6 months before, concurrently, or after initiation of ICPIs. Seventeen (59%) received a single-agent ICPI, and 12 received combination ICPIs. All of the patients received ICPIs until progression of their disease. Roughly half of the patients received thoracic RT at the same time or after ICPI therapy, while the others were treated with RT 2 weeks to 5.5 months before ICPI therapy, with a median interval of 2.2 months.


Median progression-free (PFS) and overall survival (OS) were 3.8 months and 9.2 months, respectively, with a median PFS/toxicity follow-up of 6.6 months. Radiotherapy doses ranged from 10 Gy to 70 Gy in 1 to 35 fractions.


One patient experienced possible RT/ICPI-related grade 5 pulmonary toxicity 2 weeks after completing RT. The patient, who suffered from congestive heart failure, subsequently died. Two other patients experienced possible grade 3 TRT/ICPI-associated pneumonitis, approximately 2-4 months after RT. In these cases, anti-PD-L1/CTLA-4 and anti-PD-L1 therapy were completed approximately 1 and 2 months before starting RT.


Two additional cases of grade 2 and grade 3 pneumonitis related to an anti-PD-1 agent administered before RT were also noted. Both patients were successfully treated with steroids and later received RT without any additional pulmonary toxicity.


Larger Studies Needed

Ravi Salgia, MD, PhD, the Kaplan Chair in Medical Oncology and Associate Director of Clinical Sciences at the City of Hope Comprehensive Cancer Center, Duarte, Calif., said that, while the findings are encouraging, larger trials with longer follow-up are vital.


"I think this study shows the potential for the tolerability and efficacy of this emerging type of targeted combination therapy for advanced disease. All of the research at this symposium shows how cancer therapy is moving toward precision in personalized treatment."


But while research focusing on development of new immune targets and therapies are important, it is equally important to study their potential toxicity, especially in the long-term, he told Oncology Times.


"This is exactly why studies like this are so important. People are in the process of developing or have developed standardized protocols for all of these newer therapies. Not all of them have been standardized yet, but they are evolving, and data on potential toxicity data plays an important part in that effort. Protocols are needed for oncologists, but also for internal medicine doctors with [lung cancer] patients," he noted.


"Immunotherapy can result in significant toxicity, and sometimes this toxicity is too severe for a novel treatment or approach to be useful. In lung cancer treatment, pneumonitis is always a concern, but any 'itis' is a problem."


And while data like those reported in this study are important, they are from a single institution and larger, multi-institutional studies are needed.


"In this study, the rate of adverse events was 10 percent, but 0 percent is better," Salgia concluded. "We need to make sure that toxicity is as minimal as is possible with any new approach. Efficacy lacks utility if toxicity is too high, so we really need to pay attention to these studies."


Kurt Samson is a contributing writer.