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eUpdate – Early and Locally Advanced Non-Small-Cell Lung Cancer (NSCLC) Treatment Recommendations

eUpdate – Early and Locally Advanced Non-Small-Cell Lung Cancer (NSCLC) Treatment Recommendations

Published: 04 May 2020. Authors: ESMO Guidelines Committee

Clinical Practice Guidelines

This update refers to the Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. P.E. Postmus, K.M. Kerr, M. Oudkerk, S. Senan, D.A. Waller, J. Vansteenkiste, C. Escriu and S. Peters. Ann Oncol 2017; 28 (suppl 4): iv1–iv21.

Section

Treatment of locally advanced stage (stage III); Systemic therapy

Text update

The European Medicines Agency (EMA) has approved durvalumab for the treatment of patients with locally advanced, unresectable stage III non-small-cell lung cancer (NSCLC) who have not progressed following chemoradiotherapy whose tumours express programmed death-ligand 1 (PD-L1) on ≥1% of tumour cells, although the latter was a post hoc subgroup analysis.

The recommendation is based on the phase III PACIFIC trial, in which the PD-L1 inhibitor durvalumab commenced 1–42 days post chemoradiotherapy improved both progression-free survival [PFS; median PFS 16.8 versus 5.6 months; hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.42–0.65, P<0.0001] and overall survival (OS; HR 0.68, 95% CI 0.53–0.87, P=0.00251) in 473 patients as compared with 236 patients randomised to placebo [1, 2]. The 12-month PFS rate was 55.9% versus 35.3%, and the 18-month PFS rate was 44.2% versus 27.0%, again favouring the durvalumab arm. The PFS benefit associated with durvalumab was consistent across all prespecified subgroups, as defined according to patient demographic characteristics, baseline clinicopathological features, and response to previous treatment. The PFS benefit was shown irrespective of PD-L1 expression before chemoradiotherapy. The HR was 0.59 (95% CI 0.43–0.82) for patients with a PD-L1 expression level of <25%, and the HR was 0.41 (95% CI 0.26–0.65) for patients with a PD-L1 expression level of ≥25%. Objective response rate, as assessed by blinded independent central review, was also significantly higher with durvalumab (28.4% versus 16.0%; P<0.001). At a median follow-up of 33.3 months, updated OS remained improved (stratified HR 0.69, 95% CI 0.55–0.86) [3].

A post hoc exploratory analysis of the mature survival data, requested by licensing authorities, observed that benefit with durvalumab was not evident in patients with PD-L1 expression <1%. The significance of this observation is disputed [4].

Grade 3/4 adverse events (AEs) were slightly more common with durvalumab (29.9% versus 26.1%). Pneumonia was the most common grade 3/4 AE and was observed in 4.4% of patients in the durvalumab group and 3.8% of patients in the placebo group. About 29% of patients in the durvalumab group experienced serious AEs compared with 22.6% of the placebo arm. Grade 3/4 pneumonitis or radiation pneumonitis occurred in 3.4% of the durvalumab group and 2.6% of the placebo group. Overall, safety was similar and durvalumab had no detrimental effect on patient-reported outcomes. Quality of life was evaluated as a secondary outcome and no benefit was observed [5].

Recommendation

The consolidation administration of the immune checkpoint inhibitor durvalumab 1 to 42 days after the end of chemoradiotherapy has demonstrated a survival benefit in unresectable stage III NSCLC and is recommended in patients whose tumours express PD-L1 on ≥1% of tumour cells and whose disease has not progressed following platinum-based chemoradiotherapy (as per the EMA approved indication {[I, A; European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.1 score: 4] in the intention to treat population across all PD-L1 categories}.

ESMO-Magnitude of Clinical Benefit Scale (MCBS) table for new therapies/indications in early and locally advanced NSCLCa

Therapy

Durvalumab

Disease setting

Consolidation therapy in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemo radiotherapy [1, 2, 3, 5]
NCT02125461

Trial

PACIFIC

Phase

Phase III

Control

Placebo 
PFS: 5.6 months
OS: 29.1 months
2-year OS survival 55.3%

Absolute survival gain

PFS gain: 11.2 months
Calculated estimate of OS gain: 13 monthsb
2-year OS gain: 11%

HR (95% CI)

PFS: HR 0.52 (0.42–0.65)
OS: HR 0.69 (0.55–0.86)c

QoL/toxicity

No benefit was observed

ESMO-MCBS scored

4
(Form 2a)

a EMA approvals since January 2016.
b Calculated estimate of OS gain based on PE HR 0.69.
c Median follow-up 33 months.
ESMO-MCBS version 1.1 [6]. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee.

CI, confidence interval; EMA, European Medicines Agency; HR, hazard ratio; ESMO-MCBS, ESMO-Magnitude of Clinical Benefit Scale; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival; PE; point estimate; QoL, quality of life.

References

  1. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2017;377(20):1919–1929.
  2. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379:2342–2350.
  3. Gray JE, Villegas A, Daniel D, et al. Three-year overall survival with durvalumab after chemoradiotherapy in stage III NSCLC—update from PACIFIC. J Thorac Oncol 2020;15:288–293.
  4. Peters S, Dafni U, Boyer M, et al. Position of a panel of international lung cancer experts on the approval decision for use of durvalumab in stage III non-small-cell lung cancer (NSCLC) by the Committee for Medicinal Products for Human Use (CHMP). Ann Oncol. 2019;30(2):161–165.
  5. Hui R, Ozguroglu M, Villegas A, et al. Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study. Lancet Oncol. 2019;20:1670–1680.
  6. Cherny NI, Dafni U, Bogaerts J, et al. ESMO-Magnitude of Clinical Benefit Scale Version 1.1. Ann Oncol. 2017;28:2340–2366.

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