PD-1 Rechallenge After Immunotherapy Shows Modest Activity in Older Lung Cancer Patients

Older patients with advanced non-small-cell lung cancer who have already been through a course of immunotherapy often face an uncomfortable question: is there anything left worth trying? A new retrospective study from Guilin People’s Hospital in China offers a cautiously encouraging, if preliminary, answer. Researchers analyzed 56 patients aged 60 years or older whose disease had progressed after, or whose treatment had ended because of, a previous immunotherapy regimen, and who then received a second course consisting of a PD-1 inhibitor alone. The results, published in Drugs – Real World Outcomes, showed modest but measurable antitumor activity: the objective response rate was 21.4 percent, meaning roughly one in five patients experienced meaningful tumor shrinkage, and the disease control rate, which adds patients whose tumors remained stable, reached 58.9 percent.

The study was deliberately narrow in scope. All patients were treated at a single institution between January 2019 and March 2025, and all received one of four PD-1 inhibitors approved for lung cancer in China: tislelizumab, sintilimab, camrelizumab, or pembrolizumab, each given at a fixed 200-milligram intravenous dose every three weeks. Restricting the analysis to monotherapy was a methodological choice intended to strip out the noise that combination regimens introduce, allowing the effects of renewed PD-1 blockade itself to be observed more directly. Tislelizumab was the most frequently chosen agent, used in 23 patients, followed by sintilimab in 18, camrelizumab in nine, and pembrolizumab in six. The choice of drug was made by treating physicians according to routine clinical practice rather than any protocol, and the authors stress that the study was never designed or powered to compare the four agents against one another.

Response was assessed using RECIST 1.1 criteria, the standard radiological framework for measuring tumor change on imaging. No patient achieved a complete response, but 12 had partial responses and 21 had stable disease. Five patients had no post-baseline imaging and were conservatively counted as non-responders in the primary analysis, a choice the authors acknowledge may underestimate benefit but avoids inflating the apparent activity of the treatment by excluding patients lost to assessment. In a secondary analysis restricted to the 51 patients who were actually response-evaluable, the response rate rose slightly to 23.5 percent and disease control to 64.7 percent. Among those 51 patients, the mean best percentage change in target-lesion size was a shrinkage of 1.20 percent, and one illustrative case, a 69-year-old woman rechallenged with pembrolizumab after prior immunotherapy plus chemotherapy, showed her target lesion shrinking by more than half after four cycles.

Survival outcomes told a similar story of modest but real benefit. Median progression-free survival from the start of rechallenge was 3.9 months, with a 95 percent confidence interval of 1.88 to 5.92 months, based on 42 progression or death events, corresponding to 75 percent data maturity for that endpoint. Median overall survival, the study’s primary endpoint, was 11.3 months from rechallenge, with 38 deaths recorded among the 56 patients by the data cut-off of 15 October 2025. The 12-month overall survival rate was 49.8 percent, and roughly a quarter of patients were still alive at two years. Among the 12 patients who responded, the median duration of response was 5.2 months, with a 12-month response-duration rate of 25 percent. The authors note that overall survival in this setting reflects not only the rechallenge itself but also whatever therapies patients received afterward, which in many cases included chemotherapy.

Safety findings were broadly consistent with the known profile of PD-1 blockade, though with some notable signals. Treatment-related adverse events of any grade occurred in 41 patients, or 73.2 percent, and grade 3 or worse events in 15 patients, or 26.8 percent. The most common toxicities were fatigue in 46.4 percent of patients, decreased appetite in 39.3 percent, rash in 26.8 percent, hepatic enzyme elevations in 21.4 percent, pneumonitis in 19.6 percent, and hypothyroidism in 16.1 percent. No treatment-related deaths were recorded, and immune-related events were generally manageable with corticosteroids and supportive care. What stood out were pneumonitis and hepatotoxicity, each affecting about one in five patients with nearly 9 percent experiencing grade 3 or worse events, rates above the 3 to 5 percent all-grade pneumonitis typically reported in registration trials but comparable to real-world series in older patients and those with pre-existing lung disease.

Those elevated organ-specific rates appear to have a plausible explanation in the patients’ baseline characteristics. Among the 11 patients who developed pneumonitis, five had received prior thoracic radiotherapy, seven had pre-existing pulmonary disease such as chronic obstructive pulmonary disease, interstitial lung disease, or pulmonary fibrosis, and five had a documented history of pneumonitis before rechallenge. Among the 12 patients with hepatic enzyme elevations, five had liver metastases, six had chronic liver disease or viral hepatitis, and three had abnormal liver enzymes at baseline. The authors caution that these categories overlapped and that no comparison group was analyzed, so no causal association can be drawn from these descriptive observations. Still, the pattern reinforces a practical message: careful baseline assessment and vigilant monitoring for new cough, dyspnea, or radiological changes, along with routine hepatic biochemical testing, are warranted during rechallenge in this population.

The exploratory analyses probing who benefits most yielded findings the authors interpret with deliberate restraint. In univariable comparisons, patients with an ECOG performance status of 2 had significantly shorter overall survival than those with a status of 0 or 1, at 7.8 versus 13.2 months, and patients with three or more metastatic sites fared worse than those with fewer, at 8.9 versus 14.5 months. In a three-variable multivariable Cox model, better performance status and lower metastatic burden each remained associated with a lower hazard of death, with hazard ratios of 0.59 and 0.61 respectively. But the authors emphasize these may simply reflect general prognostic factors rather than predictors of specific benefit from rechallenge. Notably, whether prior immunotherapy had been stopped for disease progression or for toxicity was not statistically significantly associated with survival after adjustment, and with only 38 deaths the model is vulnerable to overfitting.

That subgroup question carries real clinical interest. Prior research, including a study of 144 patients by Gobbini and colleagues that reported a 16 percent rechallenge response rate and 4.4-month median progression-free survival, has suggested that patients who stopped initial immunotherapy for reasons other than progression may fare better on retreatment, perhaps because their tumors retained immunological sensitivity. In the present cohort, the 18 patients who discontinued prior therapy for intolerance did show numerically higher response and disease control rates and longer median survival than the 38 who progressed, but none of the differences reached statistical significance, and the authors explicitly warn against reading the pattern as either a real difference or evidence of equivalence. PD-L1 expression, unavailable for 13 patients, could not be incorporated into the main model at all.

The limitations are substantial and the authors enumerate them candidly. This was a retrospective, single-center study of 56 patients with no comparator group, no formal sample-size calculation, and no adjustment for multiple comparisons. The decision to rechallenge was individualized by treating physicians, meaning frail patients or those with rapidly progressive disease were likely under-represented, and the observed outcomes may be more favorable than an unselected population would achieve. The six-year enrollment window introduced temporal heterogeneity in drug availability and practice patterns, chronological age alone says little about physiological reserve or frailty, and complete data from the initial immunotherapy course were unavailable for much of the cohort. The age threshold of 60 years was an operational choice aligned with United Nations and Chinese epidemiological conventions, not a biological boundary, and the study cannot support conclusions specific to patients over 75 or 80.

Within those constraints, the study adds a useful data point to a sparse evidence base. Immunotherapy rechallenge is not part of standard guidelines in non-small-cell lung cancer, yet oncologists increasingly encounter patients who have exhausted or progressed through prior options, and prior studies have reported response rates anywhere from 5 to 30 percent depending heavily on patient selection. The findings here, an objective response rate of 21.4 percent, median progression-free survival of 3.9 months, median overall survival of 11.3 months, and a toxicity profile that was acceptable but not trivial, sit squarely within that range and suggest that, in carefully selected older patients, renewed PD-1 blockade can still shrink tumors or hold disease steady for a meaningful interval. The authors are unambiguous that the results are hypothesis-generating rather than definitive, and that larger multicenter prospective studies with predefined analyses are needed before rechallenge can be recommended routinely. Until then, the study offers clinicians a benchmark for counseling older patients weighing whether a second round of immunotherapy is worth the attempt.

Subject of Research: PD-1 inhibitor rechallenge effectiveness and safety in older patients with advanced non-small-cell lung cancer

Article Title: Effectiveness and Safety of PD-1 Inhibitor Rechallenge After Prior Immunotherapy in Patients Aged ≥ 60 Years with Advanced Non-Small-Cell Lung Cancer: A Single-Center Retrospective Study

Article References: Jiang, X.-Y., Li, X., Huang, H., Pan, M., Chen, Q.-Q., & Chen, C.-Q. (2026). Effectiveness and Safety of PD-1 Inhibitor Rechallenge After Prior Immunotherapy in Patients Aged ≥ 60 Years with Advanced Non-Small-Cell Lung Cancer: A Single-Center Retrospective Study. Drugs – Real World Outcomes. https://doi.org/10.1007/s40801-026-00578-2

Image Credits: AI Generated

DOI: 10.1007/s40801-026-00578-2

Keywords: PD-1 inhibitors, non-small-cell lung cancer, immunotherapy rechallenge, older adults, retrospective study, progression-free survival, overall survival, immune-related adverse events, pneumonitis, real-world evidence, Effectiveness, Safety