Morning Dosing of Cancer Immunotherapy Extends Survival in Lung Cancer Trial

A randomized trial of 210 people with advanced lung cancer has demonstrated that the timing of immunotherapy administration significantly affects patient outcomes, with morning treatment nearly doubling progression-free survival compared to later-day dosing. The study, reported February 2 in Nature Medicine, is the first controlled trial to examine whether the timing of immune therapy affects patient outcomes.

Clinicians randomly assigned patients with late-stage lung cancer to receive the first four cycles of their drug treatment—an immune-targeted checkpoint inhibitor plus conventional chemotherapy—either in the morning to early afternoon or later in the day. Patients treated earlier went nearly twice as long without their tumors growing bigger or spreading, about 11 months in a typical case compared with 6 months, and lived nearly a year longer on average, surviving roughly 28 months versus 17 months in the late-treatment group.

The findings offer evidence that circadian biology—the body's internal clock—can shape how well cancer drugs mobilize the immune system against tumors. Previous studies had hinted at similar timing effects but emerged from retrospective analyses of patient records and were vulnerable to confounding factors such as job flexibility, travel distance and patient frailty. Randomization helps cut through those uncertainties by keeping all other aspects of care the same and varying only the timing of treatment.

Blood tests from the study offered hints as to why timing matters. Patients treated earlier in the day showed signs of a more active immune response, with higher levels of cancer-fighting T cells than those treated later. Notably, earlier dosing did not increase rates of immune-related side effects, suggesting that timing may boost the immune system's attack on tumors without raising the risk of autoimmune reactions.

The results point to a simple scheduling change as a low-cost way to improve outcomes for cancer patients without altering drugs, doses or other treatment parameters. The work could also influence how future cancer drugs are tested in clinical trials, with investigators deliberately giving therapies earlier in the day to make meaningful clinical benefits easier to detect.

Hospital logistics and patient scheduling could pose practical challenges to widespread adoption of morning dosing. However, if the benefits are confirmed in additional randomized trials across other types of cancer, other immunotherapy drugs and in other health care settings, cancer clinics will need to make infrastructure changes to allow this to become standard practice.

While checkpoint inhibitors have revolutionized cancer treatment, they can cause severe inflammatory side effects, including arthritis, which affects at least 5% of treated cancer patients and significantly impacts quality of life. The arthritis may persist even after the checkpoint inhibitor is stopped and may require treatment with drugs to suppress the immune system.

The REmission induction of Arthritis caused by Cancer ImmunoTherapy (REACT) trial, led by the University of Birmingham and delivered through the National Institute for Health and Care Research Birmingham Biomedical Research Centre, is now recruiting 70 patients across sites in the UK. The trial aims to find whether initial treatment with anti-TNF (anti-Tumour Necrosis Factor) therapy works to better control this type of arthritis while not significantly interfering with cancer therapy.

Immune checkpoint inhibitors are drugs that block 'off' signals in the immune system to help it fight cancer. The current treatment approach for arthritis that has resulted from checkpoint inhibitor treatment is to typically start with steroid tablets, then gradually try other treatments if these fail. Anti-TNF is currently often the last treatment used. Anti-TNF is a drug that blocks an immune protein called Tumour Necrosis Factor.

TNF inhibitors have good evidence for other types of arthritis but there is no evidence for patients with checkpoint inhibitor-induced arthritis to safely guide initial treatment strategy, so this trial will be the first to test the effects of immune suppressing drugs on cancer outcomes in response to checkpoint inhibitors.

The discontinuation of checkpoint inhibitor therapy as a result of primary or acquired resistance or intense immune-related adverse events remains a serious problem. Reintroduction of checkpoint inhibitors, known as immune checkpoint inhibitor rechallenge, is a promising but complicated approach to treatment that currently lacks standardized guidelines.

Key predictors of successful rechallenge include a lasting response to initial checkpoint inhibitor therapy (progression-free survival 6 months and preferably 12 months), a long treatment-free interval (6 months or more), good baseline-level performance status, and the absence of previous immune-related adverse events (symptoms resolving to grade 1 or lower). The objective response rates can be improved by combination therapy with chemotherapy, anti-angiogenic therapy, or local radiotherapy, which can positively adjust the tumor microenvironment. The recurrence of immune-related adverse events after rechallenge remains a significant issue, with 20-60% reported rates, which often requires irreversible discontinuation after severe toxicity.

For undifferentiated pleomorphic sarcoma, there is currently no consensus on the best approach for using checkpoint inhibitors. Some clinicians advocate for using them upfront as a non-toxic treatment, which can occasionally have remarkable results. However, others are more cautious, pointing to the lack of randomized evidence and preferring to use them only in refractory settings after standard agents. The phase 3 ECOG-ACRIN 7222 trial, if positive, could support using doxorubicin in combination with pembrolizumab as a frontline therapy.

Research published in the journal Cell has mapped out how genetic mutations allow tumors to build immune barriers, a discovery that could explain why modern cancer treatments often fail in patients whose cancer has spread. The study found that the loss of certain tumor suppressor genes triggers a massive buildup of collagen. This excess collagen makes the tumor structure so dense that it acts like a wall, preventing T cells from reaching and killing the cancer.

The team identified a specific molecule called LOXL2 as the architect of this barrier. In tests on mice, researchers found that by blocking LOXL2, they could dissolve the collagen wall. This allowed T cells to penetrate the tumor and significantly boosted the power of immunotherapy drugs. Such a strategy proved successful to enhance the antitumor effects of immunotherapy in mice with various tumor metastases.

The study also utilized machine learning to simplify how doctors might predict a patient's success with treatment. The team developed a model that uses just 30 characteristic genes to predict whether a metastatic site will respond to immunotherapy, achieving an accuracy rate of over 75 percent. The researchers are now moving toward clinical evaluations to see if the results found in mice can be replicated in humans.