No down-side to starting durvalumab immediately after chemoradiation for unresectable stage III non-small cell lung cancer—some answers but more questions

The recent publication of TORG1937 (DATE study) in Clinical Cancer Research by Nakamichi et al. is a phase II clinical trial examining the safety and efficacy of initiating consolidation durvalumab immediately following concurrent chemoradiation therapy (CCRT) for unresectable stage III non-small cell lung cancer (NSCLC) (1). The results build on the landmark PACIFIC trial (2), which established consolidation durvalumab as the standard of care for patients with unresectable stage III NSCLC who showed no progression after CCRT, by demonstrating a significant improvement in their progression-free survival (PFS). A subsequent PACIFIC report in 2018 also showed a significant benefit in overall survival, reinforcing its widespread adoption (3).

In a subgroup analysis of PACIFIC, the 120 patients who started durvalumab within 14 days of completing CCRT experienced better outcomes [hazard ratio (HR) =0.39] compared to those who began after 14 days (HR =0.63), prompting the Japanese Thoracic Oncology Research Group (TORG) to test the efficacy and safety of initiating durvalumab as close to the completion of CCRT as possible. Their multi-institutional study enrolled 50 patients aged 20–74 years with biopsy-proven unresectable stage III NSCLC. Eligible patients, demonstrating complete response, partial response, or stable disease after 60 Gy of CCRT, began durvalumab (10 mg/kg) within 1–5 days after completion of CCRT, and continued receiving durvalumab biweekly for up to 12 months.

The baseline characteristics of the DATE study were comparable to the PACIFIC cohort, although the DATE group had a higher proportion of males (87% vs. 70%) and was comprised of a completely Japanese population, compared with only 27% of patients who identified as Asian in the PACIFIC cohort. Safety profiles were similar: while 78.7% of DATE patients experienced pneumonitis—higher than the 33.9% in PACIFIC—only 4.3% were grade 3 or higher (similar to PACIFIC’s 3.4%). Still, the DATE cohort also had a higher rate of grade 3 or greater lung infections (14.9% vs. 4.4%). And while the TORG group made note that the higher rate of respiratory complications was similar to the results in the Japanese subgroup of PACIFIC, these respiratory concerns remain unexplained and would require a randomised trial to investigate more thoroughly. Is it possible that susceptibility to immune-related adverse events such as pneumonitis might be influenced by ethnic or ancestral factors such as differences in human leukocyte antigen (HLA) haplotype? This has been documented in some studies, and is an area of active research with respect to the risk of immunotherapy use across different populations (4,5).

After a median follow-up of 14 months, the DATE trialists reported a median PFS of 12.7 months and a 1-year PFS of 75%. Although these results appear comparable to those reported by the PACIFIC investigators, cross-trial comparisons can be challenging and fraught with confounders. For example, the 16.8 months median PFS and the 55.9% 1-year PFS reported by the PACIFIC investigators were estimated from the time of randomization to durvalumab or placebo rather than from the time of registration to CCRT as reported by the DATE trialists. As such, it is difficult to discern the degree of similarity between these PFS results.

Another area of interest is the optimal treatment combinations and sequences offered for patients with locally advanced NSCLC, particularly those who present with stage III disease. In the DATE trial, 37 patients had either a complete response or partial response, close to half of the cohort had stage IIIA disease, and nearly 40% of patients had tumors that expressed PD-L1 in at least 50% of their tumor cells. Is it possible that at least some of these patients might have been candidates for neoadjuvant chemoimmunotherapy followed by surgical resection? How was resectability determined in this cohort of patients? Definitions of unresectability have been frustratingly heterogeneous across both clinical trial and real-world contexts. It varies from the presence of fixed or bulky lymph nodes, to involvement of major vascular structures, the trachea, esophagus, or spine. Indeed, the main principle that has remained constant is that surgery should be embarked upon primarily when an R0 resection is deemed feasible, and that R1 and R2 resections are associated with poor survival.

In this regard, recent perioperative and neoadjuvant chemoimmunotherapy trials such as Checkmate 816 (6), Keynote 671 (7), AEGEAN (8), and Checkmate-77T (9) have all shown promising results particularly in patients with stage III disease. Nonetheless, there remains significant nihilism in pursuing surgery in cases with significant nodal disease at the time of presentation. While there has not been a direct comparison of the two strategies (CCRT/immunotherapy vs. neoadjuvant chemoimmunotherapy plus surgery), one can argue that surgical resection remains the best way of determining tumor response to therapy and true residual disease burden, clearance of local disease, and providing important prognostic information on these varied tumors. So while there may be no down-side to starting durvalumab immediately after CCRT for unresectable stage III NSCLC, it remains essential to select these patients thoughtfully with input across specialties.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1858/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1858/coif). N.K.A. reports research funding from AstraZeneca, Janssen Pharmaceuticals and New York Genome Center; and honoraria from AstraZeneca and Regeneron. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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