Neoadjuvant chemoimmunotherapy is superior to neoadjuvant chemotherapy in patients with resectable NSCLC across surgical, pathological and efficacy outcomes, a systematic review has concluded.

And in a finding with major potential implications, the data also suggest event-free survival benefits from neoadjuvant chemoimmunotherapy in those with tumour PD-L1 levels below 1%, according to the authors.

Billed as the most comprehensive review on the topic date, the analysis incorporated data from 43 studies published since 2013 – including eight RCTs – involving 5431 adult patients with resectable NSCLC.

For the RCTs, neoadjuvant chemoimmunotherapy was favoured over neoadjuvant chemotherapy in terms of pooled overall survival (HR: 0.65), event-free survival (HR: 0.59), major pathological response and complete pathological response.

Improvements in EFS were found across age, sex, and histology (squamous and nonsquamous cancer) groups, as well as for those with PD-L1 levels <1%, 1%-49%, and ≥50%.

On the other hand, the OS benefit was restricted to the subgroup with a PD-L1 level of 1% or greater based on the current maturity of OS data, the researchers reported in JAMA Oncology (link here).

“This highlights that the restriction in the approval of neoadjuvant chemoimmunotherapy exclusively for patients with a PD-L1 level of 1% or greater by the European Medicines Agency was based on a subgroup analysis from a single trial (CheckMate 816) and that the available evidence now suggests that this patient population may have an EFS benefit with neoadjuvant chemoimmunotherapy,” wrote the authors, led by Dr Mark Sorin of the Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal.

“It will be important to assess whether this translates into an OS benefit as the number of studies reporting OS and the follow-up time for these studies increase.”

Other findings were that neoadjuvant chemoimmunotherapy was associated with a reduced risk of progression precluding surgery, but an increased risk of adverse events that did so.

Across all RCTs, 7-22% of patients were not resected in chemoimmunotherapy arms, the authors added.

“While it is possible that patients who progressed on therapy could have benefited from up-front surgery, these patients were likely to develop early metastasis even if resected up front,” they wrote.

“There remains a clear gap in our understanding of the relative benefits associated with neoadjuvant vs adjuvant strategies for this patient population, although significant challenges exist around the feasibility of trials aimed at resolving this open question.”

Findings shed light on chemoimmunotherapy ‘revolution’: experts

The data on the role of neoadjuvant chemoimmunotherapy in PD-L1-negative tumours were described as some of the most significant to emerge from the analysis in an accompanying editorial (link here).

Besides the subgroup analysis of CheckMate-816, similar trends of higher efficacy with increasing PD-L1 expression had been observed in two perioperative randomised phase 3 trials AEGEAN and KEYNOTE-671, wrote the authors.

A longer follow-up of these studies should confirm those findings and whether the survival benefit seen might be considered clinically significant, they wrote. However, to date, the only study with a 3-year follow-up, the CheckMate-816 study, exceeded the more than 5% improvement of survival at three years’ follow-up or longer in both PD-L1-negative and PD-L1-positive tumours.

“An important aspect of novel neoadjuvant therapies is the impact on planned surgery in terms of delays, type of surgery, and complications,” they added.

“Collectively, the results of the present meta-analysis suggest that neoadjuvant chemoimmunotherapy is safe, with no significant differences in the relative risk for grade 3 to 4, grade 5, and total adverse events compared with chemotherapy alone.”

Surgical outcomes were also comparable, the authors noted.

The next frontier would be improved testing, with liquid biopsy recently emerging as a potential novel biomarker for minimal residual disease (MRD) detection to identify patients at higher risk of relapse after surgery and thus potential use for decisions on whether to escalate or de-escalate treatment.

“The most significant challenge for clinical implementation of liquid biopsy in this setting is the high heterogeneity of the assays used to date and the relatively still low sensitivity to detect MRD-positive patients,” they added.

“Integration of multiomics analyses, combining genomics, methylomics or fragmentomics, can increase the sensitivity of currently available tests, reducing the risk of false-negative results.”

“Finally, the integration with other known prognostic and/or predictive factors, such as MPR/pCR, PD-L1 expression, and clinical other clinicopathological features (spread though air spaces, lymphovascular invasion, etc) will likely further refine the accuracy of these assays, favouring the implementation of risk scores that can drive the therapeutic decision-making.”