A new systematic review and meta-analysis published in The Oncologist in June 2024 provides evidence that rechallenge with immune checkpoint inhibitors (ICIs) may be a feasible strategy for some cancer patients who previously discontinued treatment. The study, conducted by researchers in China, suggests that ICI rechallenge is associated with relatively low toxicity, similar efficacy to initial treatment, and potential survival benefits in certain patient populations.
This meta-analysis synthesized data from 36 retrospective studies involving a total of 2,026 patients with various advanced cancers, including non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC). The researchers aimed to evaluate the safety, efficacy, and survival outcomes of ICI rechallenge in patients who had previously stopped treatment due to immune-related adverse events (irAEs) or disease progression.
The study was funded by grants from several Chinese research programs, including the Taishan Scholars Program of Shandong Province and the National Natural Science Foundation of China. It was published online in The Oncologist on June 28, 2024.
To be included in the analysis, studies had to enroll adult patients with solid tumors who had been treated with ICIs and then resumed treatment after a previous interruption due to toxicity or progression. The researchers excluded studies where patients stopped ICI therapy for other reasons or where detailed information on irAEs or treatment outcomes was not provided.
The primary outcomes of interest were the incidence of all-grade and high-grade irAEs, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The analysis compared these outcomes between initial ICI treatment and rechallenge.
Key findings from the meta-analysis include:
- Safety: ICI rechallenge was associated with a significantly lower incidence of all-grade irAEs (OR 0.05, 95% CI 0.02-0.13) and high-grade irAEs (OR 0.37, 95% CI 0.21-0.64) compared to initial ICI treatment.
- Efficacy: There was no significant difference in ORR (OR 0.69, 95% CI 0.39-1.20) or DCR (OR 0.85, 95% CI 0.51-1.40) between rechallenge and initial treatment.
- Survival: Patients receiving ICI rechallenge had significantly improved PFS (HR 0.56, 95% CI 0.43-0.73) and OS (HR 0.55, 95% CI 0.43-0.72) compared to those who permanently discontinued ICI therapy.
Importantly, subgroup analyses revealed that outcomes differed based on the reason for initial ICI discontinuation. For patients who stopped due to irAEs, rechallenge showed similar safety and efficacy to initial treatment. However, for those who discontinued due to disease progression, rechallenge was associated with a significant increase in high-grade irAEs (OR 4.97, 95% CI 1.98-12.5) and decreased ORR (OR 0.48, 95% CI 0.24-0.95).
The study has several limitations that should be considered when interpreting the results. First, all included studies were retrospective, introducing potential biases. Second, few studies reported survival outcomes, limiting the ability to conduct comprehensive subgroup analyses for PFS and OS. Additionally, most studies did not provide details on specific types of irAEs, preventing further analysis based on toxicity profiles.
Despite these limitations, the authors conclude that ICI rechallenge may be a feasible strategy for some cancer patients, offering relative safety, similar efficacy to initial treatment, and potential survival benefits. However, they emphasize that the decision to rechallenge should be carefully weighed on an individual basis, considering potential risks and benefits.
The findings of this meta-analysis could have significant clinical implications for oncologists considering ICI rechallenge in patients who previously discontinued treatment. The results suggest that rechallenge may be a viable option, particularly for patients who stopped initial treatment due to irAEs. However, caution is warranted for those who discontinued due to disease progression, given the higher risk of severe toxicities and lower response rates observed in this subgroup.
Additionally, the survival benefit associated with ICI rechallenge highlights the potential importance of resuming immunotherapy in appropriate patients, rather than permanently discontinuing treatment. This finding challenges the notion that patients who have not yet responded to initial ICI therapy are unlikely to benefit from rechallenge.
The study also raises important questions about the underlying mechanisms of ICI response and resistance. The authors speculate that the immunotherapy microenvironment may "settle down" after several months or years, potentially endangering initial gains and leading to disease relapse. This hypothesis warrants further investigation in future studies.
While these results are promising, the authors emphasize the need for large-scale prospective studies with strict inclusion criteria to verify their findings. Such studies could help establish more definitive guidelines for ICI rechallenge in clinical practice.
In conclusion, this comprehensive meta-analysis provides valuable insights into the safety, efficacy, and survival outcomes associated with ICI rechallenge in cancer patients. The findings suggest that rechallenge may be a viable strategy for some patients, but careful consideration of individual factors is crucial. As immunotherapy continues to evolve as a cornerstone of cancer treatment, further research in this area will be essential to optimize patient outcomes and inform clinical decision-making.
References
Liu SJ, Yan LJ, Wang HC, et al. Safety, efficacy, and survival outcomes of immune checkpoint inhibitors rechallenge in patients with cancer: a systematic review and meta-analysis [published correction appears in Oncologist. 2024 Nov 4;29(11):e1628. doi: 10.1093/oncolo/oyae224]. Oncologist. 2024;29(11):e1425-e1434. doi:10.1093/oncolo/oyae134
