RT-IMMUNOTHERAPY COMBINATION

Immune-related adverse events (IRAEs) are not more likely to occur when patients with metastatic lung cancer receive a combination of immunotherapy with checkpoint inhibitors (CPIs) and thoracic radiotherapy (TRT) compared with those who receive CPI therapy alone, a retrospective cohort study from an academic medical center in the United States suggests.

"Checkpoint inhibitors have transformed the management of metastatic lung cancer, resulting in significant improvements in overall survival and progression-free survival as compared to chemotherapy, so the vast majority of patients with metastatic lung cancer will receive checkpoint inhibitors, either in the first line for patients with PD-L1 expression ≥50%, or in second line after progression on chemotherapy," senior author Florence Keane, MD, Massachusetts General Hospital in Boston, told Medscape Medical News in an email.

"But, as both checkpoint inhibitors and thoracic radiotherapy are associated with a risk of pneumonitis, our concern was that receipt of both therapies might significantly increase the risk of IRAEs, particularly pneumonitis," she added.

"However, we found that there was no significant difference in the rates of IRAEs, including pneumonitis, between patients who received thoracic radiotherapy in addition to checkpoint inhibitors, so we were reassured that receipt of [the combination] did not significantly increase risk of IRAEs in patients who received thoracic radiotherapy after or between cycles of CPIs," Dr. Keane concluded.

The research letter was published online September 27, 2017 in JAMA Oncology.

The analysis included 164 patients with metastatic lung cancer, almost all of whom had non-small cell lung cancer (NSCLC). All patients received programmed cell death 1 or programmed cell death 1 ligand (PD1/PD-L1) inhibitors at the Massachusetts General Hospital.

In addition, 73 patients also received TRT, and 91 patients did not. Of patients who received the combination of CPIs and TRT, 49% had adenocarcinoma, compared to 75% of those who received CPI therapy alone (P = .001).

However, only a small proportion of patients in either group (4% in the combination group and and 16% in CPI therapy alone group) had evidence of a targetable mutation (P = .01), the investigators note.

Rates of IRAEs of grade 2 or higher were very similar between the two groups, at 13.7% for the additional TRT group vs 15.4% for the non-TRT group. There was no statistical difference in any of the IRAE endpoints that were examined.

Table. IRAEs Rates by Study Sndpoint

	Pneumonitis of All Grades	Pneumonitis of Grade 2 or Higher
CRIs plus TRT	8.2%	4.1%
CRI alone	5.5%	3.3%

Median TRT dose was similar between those patients who developed pneumonitis and those who did not, at 52.8 Gy vs 50.4 Gy, respectively, the authors add.

Perhaps noteworthy as well, the majority of patients received radiotherapy several months prior to being treated with a CPI, and the PD1/PD-L1 inhibitor was introduced at a median interval of 8.6 months after patients had undergone TRT therapy, the investigators point out.

"Median overall survival was 12.1 months," they add. On multivariate analysis, all-cause mortality was 55% lower in patients who developed grade 2 or higher IRAEs (P = .03).

The same multivariate analysis showed that each additional line of chemotherapy was associated with an increase in mortality risk, Dr Keane and colleagues observe.

For patients who received the combination of TRT plus CPIs, there was a 34% reduction in all-cause mortality, but the difference between this group and the non-TRT group did not quite reach statistical significance (P = .06).

Improved Survival

As Dr Keane explained, there are a number of reasons why survival rates were higher for patients who developed toxicities of grade 2 or higher in the current series compared to patients who did not develop IRAEs. For one, the risk for toxicity may be related to duration of exposure to immunotherapy.

"As we noted, it is likely that patients who are responding to immunotherapy will continue to receive treatment, thereby increasing the risk of potential toxicities," she elaborated.

Another explanation could be that some patients are prone to develop inflammatory responses when receiving a CPI, resulting in development of IRAEs and improved durability of treatment response.

In a retrospective analysis in melanoma patients, for example, investigators reported an association between the development of treatment-related adverse effects and overall response rate as well as overall survival, even when controlling for the number of cycles of CPI.

"Our data are hypothesis generating, and prospective studies in both the metastatic and definitive setting are warranted to identify the optimal timing of radiotherapy in conjunction with immunotherapy and to monitor potential toxicities," Dr Keane concluded.

The recent PACIFIC trial demonstrated a significant improvement in progression-free survival with the use of adjuvant durvalumab after definitive chemoradiotherapy in patients with inoperable stage III NSCLC, as reported by Medscape Medical News. 

As such, Dr Keane predicts that CPIs are poised to move into the management of nonmetastatic NSCLC as well.

Dr Keane has disclosed no relevant financial relationships.

JAMA Oncol. Published online September 27, 2017. Full text