The ‘right’ timing for durvalumab after chemoradiation in stage III non-small cell lung cancer

Since the 2017 report of the PACIFIC trial, a new standard for unresectable stage III non-small cell lung cancer (NSCLC) has been established with durvalumab for 1 year as a consolidation for chemoradiation (1). The coprimary endpoints of progression-free survival (PFS) and overall survival (OS) were achieved and an updated OS [hazard ratio (HR) =0.72; 95% confidence interval (CI): 0.59 to 0.89; median OS (mOS): 47.5 vs. 29.1 months] and PFS [HR =0.55; 95% CI: 0.45 to 0.68; median PFS (mPFS): 16.9 vs. 5.6 months] stayed consistent with the primary analyses (2). Adverse events of any cause or grade were reported in 96.8% of the patients randomized to durvalumab and 94.9% of those randomized to placebo. In the updates, the safety profile was consistent with those previously reported. Discontinuation of the trial regimen because of adverse events was 15.4% vs. 9.8%, respectively. The prevailing adverse events that caused the discontinuation of the trial regimen were pneumonitis (4.8% vs. 2.6%), radiation pneumonitis (1.3% vs. 1.3%) and pneumonia (1.1% vs. 1.3%) (3).

The risk of pneumonitis was initially one of the main concerns for safety and efficacy, however in an exploratory analysis, pneumonitis predominantly occurred with low-grade severity and efficacy appears to be maintained irrespective of the occurrence of pneumonitis (4). Another more important relevant factor was the timing of durvalumab administration. In the pivotal study, durvalumab could be administered up to 42 days after the completion of chemoradiation and a trend toward better outcomes was observed in patients randomized before 14 days (1,3).

In this installment, Nakamichi et al. reported the results of the phase II TORG1937/DATE study, which evaluated the use of durvalumab up to 5 days after the last radiation dose. A prospective, single-arm, open-label, multicenter study, worked in 16 centers in Japan. Recruited patients were assigned to the protocol treatment consisting of concurrent chemoradiotherapy (CCRT) with two cycles of platinum-based chemotherapy and thoracic radiation therapy (TRT) (60 Gy/30 Fr) followed by durvalumab consolidation treatment from the day after the final radiation dose for up to 1 year. From January 2020 to August 2020, 50 patients were recruited (5).

The study met its primary endpoint with a 1-year PFS of 75.0% from registration. The mPFS was 14.2 months and the intervention was well tolerated. Pneumonitis was found in 78.7% of any grade and 4.3% in grade 3/4. Up to this first analysis, there was no treatment grade 5 adverse event reported. Interestingly, overall response rate (ORR) was 78.7% and no patient had progressive disease as first response, which reflects the initial role of chemoradiation as well. The 1-year OS after durvalumab initiation was 97.4%. Few reports exist on the exact timing for durvalumab initiation. This finding is consistent with what was reported in a systematic review and meta-analysis, which concluded that there is no significant risk of pneumonitis or decrease in PFS when time interval is <42 days (6). In the PACIFIC-KR, although numerically longer real-world PFS (rwPFS) in the group of patients with durvalumab starting ≤42 days, it was not statistically significant (7). Also, the veteran database report, mentioned in the discussion did not find an association between PFS and OS with the use of durvalumab up to 120 days (8).

It is notable that in this trial, TRT was given without prophylactic mediastinal irradiation and the volume of lung receiving 20 Gy (V_{20 Gy}) under 35% was noted as a selection criterion, to avoid the risk of severe pneumonitis. In a retrospective analysis by Diamond et al., pneumonitis rates were higher for patients with V_{20 Gy} equal or more the 30%, mean lung dose more than 18 Gy and mean heart dose equal or more than 10 Gy (9). Vansteenkiste et al. found that patients with pneumonitis were more likely to be Asian, irrespective of the use of durvalumab (10).

In a recent systematic review, meta-analysis, and meta-regression of 26 articles by Zhang et al., they found that the incidence of pneumonitis was higher in the Asian population and with increasing age. Conversely, a longer interval between CRT and durvalumab, as well as higher PD-L1 expression levels (≥50%), were associated with a lower incidence of pneumonitis (11). In the TORG1937/DATE study, patients 75 years old or older were excluded.

Despite the small sample size, this study contributes with prospective data about the timing for durvalumab after concomitant chemoradiation and its safety and efficacy, immediately after the last radiation therapy and up to 5 days. The final analysis is expected to yield further results for long-term follow-up and to identify prognostic factors for efficacy and safety. Additionally, outcomes for patients with EGFR and ALK mutations are of particular interest due to the scarcity of prospective evidence in this population.

The perfect timing is still under debate; however, all these trials support that CCRT followed by 1-year durvalumab consolidation continues to be the standard of care for unresectable stage III NSCLC. Further information regarding factors that could help us to attune to the patients that could benefit the most and with the lower incidence of AEs, is still pending. Last but not least, how could we identify the patients who might not need adjuvant durvalumab/overtreatment or the patients who will lack the benefit from the beginning?

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-42/coif). T.S. received payment or honoraria from Astra Zeneca, Roche, Janssen, Pfizer, MSD, and Novartis; support for attending meetings and/or travel from Merck and Janssen; was on the Data Safety Monitoring Board or Advisory Board of Merck, Novartis, and MSD; and played leadership or fiduciary role in Panamanian Society of Oncology. P.G. received personal fees from Janssen, MSD, Novartis, Medscape, Takeda, TouchTime, and Medscape; support for attending meetings and/or travel from Astra Zeneca, Roche, and Janssen; and was on the Advisory Board of Abbvie, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and Takeda, Steering Committee of Novartis, and IO Biotech IO102-Janssen. The authors have no other conflicts of interest to declare.

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