Update: On Feb. 19, Nature Medicine said it was looking into concerns about data and methods in this study.
Over the last few years, researchers have noticed that cancer patients who get immunotherapy infusions in the morning seem to do significantly better than those who get treated later. Many scientists, even some who had published such observations, were doubtful that time of day could truly make a big difference.
“I was skeptical of this phenomenon even though we’ve replicated it in our hands,” said Sumanta Pal, a medical oncologist and cancer researcher at City of Hope who has conducted one such study. Income, location, frailty, and more could bias certain patients towards a morning or afternoon time, skewing the results of retrospective studies. “There’s a whole cadre of potential explanations for why we saw what we saw,” Pal said.
But a new randomized trial published Monday in Nature Medicine is drawing renewed attention to the idea that infusing immunotherapy in the morning might be better than the afternoon. In the trial, advanced lung cancer patients who got chemo and immunotherapy infusions before 3 p.m. had a 60% reduction to the risk of progression compared to those who received infusions after 3 p.m. That result, while not fully convincing to skeptics, is raising eyebrows.
“It’s powerful to see randomized data supporting this, and definitely behooves further investigation,” said Pal, who did not work on the study.
The idea that simply changing when physicians give immunotherapy infusions can lead to dramatic improvements in cancer is a compelling one. In theory, such a change could easily improve the lives of cancer patients without additional cost or toxicity, said Yongchang Zhang, a cancer researcher and oncologist at Central South University in Changsha, China, and the senior author on the paper.
When Zhang started the trial, there had already been some observations in retrospective studies that patients who got morning immunotherapy infusion times did dramatically better than those who got late afternoon ones. But, like Pal and other experts, Zhang agreed certain biases could tilt the results in favor of the morning patients. “If you want to validate, you need a randomized trial to round out the bias,” Zhang said.
So he and his colleagues randomized 210 patients with stage 3C or stage 4 non-small cell lung cancer to get standard of care chemotherapy plus an immunotherapy drug, either pembrolizumab or sintilimab, before 3 p.m or after 3 p.m. Those who got the early infusions had a progression-free survival of 11.3 months and an overall survival of 28 months, while those with later infusions had a progression-free survival of 5.7 months and an overall survival of 16.8 months.
“It’s amazing to see that,” Zhang said. “No need to spend a lot of money to buy additional drugs, and you can get a better outcome.”
Not everyone is convinced, though. For one, the sample size is small, with just 105 patients per arm. Biases might still exist in the two arms of the trial as well, City of Hope’s Pal said. The investigators screened more than 400 patients for the trial, but randomized fewer than half, which could lead to some selection bias going into the trial in the first place.
“You would think that randomization would account for the differences,” Pal said. “If you dig deeper, many said they wouldn’t be compliant with the subscribed regimen of timing. There’s a substantial amount of attrition, and it can still lead to some imbalance.”
Why morning infusions would make a difference for immunotherapy is another open question. Some mouse studies have suggested that immune cells seem to follow a circadian rhythm, with some cells trafficking through the blood more at different times. It’s possible that T cells, the main cancer killing cell that immunotherapy drugs like pembrolizumab target, are more active or infiltrate the tumor better in the morning, Central South University’s Zhang said.
That hypothesis is puzzling to experts who point out that the half-life of pembrolizumab is over three weeks long. So, the drug is in the body morning and night for weeks. “We do not know the real mechanism, but we will work on this area,” Zhang said.
While the study is a signal that time of day for immunotherapy infusion is worth investigating further, Roy Herbst, the deputy director of the Yale Cancer Center, said he’s not going to change practice based on the trial. “It’s intriguing. This is maybe a wake-up call to look at it more. Do I need to double my staff in the morning at the hospital so everyone can be treated in the morning? I’m not ready to do that yet,” Herbst said. “It wouldn’t be feasible to do.”
Though as a patient, Herbst said, if you have the flexibility to take a morning slot then you might as well get in early.
“Why not?” he said. But, he added, don’t stress if you can’t do mornings just on account of this study.
